SUMMARY OF SAFETY AND EFFECTIVENESS DATA

# GENERAL INFORMATION

Device Generic Name: tisilfocon A rigid gas permeable contact lens

Device Trade Name: Menicon Z™ (tisilfocon A) rigid gas permeable (RGP)
contact lens

> Applicant's Name and Address: Menicon Co., Ltd.
>
> 21-19 AOI, 3-CHOME, NAKA-KU
>
> NAGOYA, AICHI 460-0006
>
> JAPAN
>
> Date(s) of Panel Recommendation: None
>
> Premarket Approval (PMA) Application
>
> Number: P990018/S2
>
> Date of Notice of Approval to Applicant: July 12, 2002

I.  **INDICATIONS FOR USE**

> Menicon Z™ (tisilfocon A) spherical, aspheric, prism ballast toric and
> prism ballast multifocal lenses are indicated for daily wear for the
> correction of refractive error (myopia, hyperopia, presbyopia and/or
> astigmatism) in aphakic and non-aphakic persons with non-diseased
> eyes.
>
> Menicon Z™ (tisilfocon A) spherical, aspheric, non-prism ballast toric
> and non-prism ballast multifocal lenses are indicated for extended
> wear (from 1 to 30 days between removals for cleaning and disinfection
> of the lenses, as recommended by the eyecare professional) for the
> correction of refractive error (myopia, hyperopia, presbyopia and/or
> astigmatism) in non-aphakic persons with non-diseased eyes.
>
> The lens may be prescribed in spherical and aspheric powers ranging
> from -25.00 D to +25.00 D for daily wear and ‑25.00 D to +8.00 D for
> up to 30 days extended wear. Toric lenses are designed to correct up
> to 5.00 D of astigmatism and multifocal lenses to provide up to +3.00
> D of reading add power for up to 30 days extended wear.

The lens may be disinfected using a chemical disinfection system only.

> (The Menicon Z™ (tisilfocon A) rigid gas permeable contact lens was
> cleared for daily wear under K962006, K970019 and K972443.)

#  {#section .unnumbered}

# CONTRAINDICATIONS

> Menicon Z™ (tisilfocon A) contact lens should not be uses when any of
> the following conditions exist:

-   Acute and subacute inflammation or infection of the anterior segment
    of the eye

-   Any eye disease, injury, or abnormality that affects the cornea,
    conjunctiva, or eyelids

-   Severe insufficiency of lacrimal secretion (dry eyes)

-   Corneal hypoesthesia (reduced corneal sensitivity)

-   Any systemic disease that may affect the eye or be exaggerated by
    wearing contact lenses

-   Allergic reactions of ocular surfaces or surrounding tissues that
    may be induced or exaggerated by wearing contact lenses or use of
    contact lens solutions

-   Allergy to any ingredient, such as mercury or Thimerosal, in a
    solution which is to be used to care for the Menicon Z™
    (tisilfocon A) Contact Lens

-   Any active corneal infection (bacterial, fungal, or viral)

-   If eyes become red or irritated

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-   Incomplete healing following eye surgery

II. **WARNINGS AND PRECAUTIONS**

The warnings and precautions can be found in the device labeling
(attached).

# DEVICE DESCRIPTION

> The Menicon Z™ (tisilfocon A) Rigid Gas Permeable Contact Lens is
> available as a daily wear spherical, aspheric, prism ballast toric or
> prism ballast multifocal design and as an extended wear lens for up to
> 30 days/29 nights in spherical, aspheric, non-prism ballast toric and
> non-prism ballast multifocal designs.
>
> The lens material (tisilfocon A) is a thermoset copolymer derived from
> fluoro-methacrylate and siloxanylstyrene, bound by crosslinking
> agents. The lens is available in a light blue tint. The blue lens is
> tinted with color additive D & C Green No. 6. Also, a UV absorber
> (Benzotriazol) is added as an additive during the manufacturing
> process.

III. **ALTERNATIVE PRACTICES AND PROCEDURES**

> The alternative practices and procedures to correcting vision by
> wearing the Menicon Z™ rigid gas permeable lenses include wearing
> other daily and extended wear rigid gas permeable contact lenses, soft
> contact lenses for daily and extended wear, spectacles, and corrective
> surgeries such as radial keratotomy, photorefractive keratectomy and
> LASIK.

IV. **MARKETING HISTORY**

## United States

> The Menicon Z™ (tisilfocon A) rigid gas permeable contact lens has
> been marketed in the United States for daily wear since October of
> 1996. The lens was approved for 7 day extended wear under PMA P990018
> on July 11, 2000.

## International

> The Menicon Z™ (tisilfocon A) rigid gas permeable contact lens is
> approved in Japan for daily and 7 day extended wear and in France and
> Germany for daily and extended wear up to 30 days.

V.  **POTENTIAL ADVERSE EFFECTS OF DEVICE ON HEALTH**

> Potential adverse effects on health associated with extended wear
> contact lenses include eye problems such as corneal ulcers, epithelial
> microcysts, infiltrates and endothelial polymegathism. The risk of
> corneal ulcer has been shown to be greater among users of extended
> wear contact lenses than among users of daily wear contact lenses. The
> risk of extended wear users increases with the number of consecutive
> days that the lenses are worn between removals, beginning with the
> first overnight use. In addition, smoking increases the risk of
> corneal ulcers for contact lens users, especially when lenses are worn
> overnight or while sleeping. Strict compliance with the proper lens
> care regimen and wearing schedule is essential in minimizing risk.

VI. **SUMMARY OF PRECLINICAL STUDIES**

> The device is unchanged from that approved in the original PMA,
> P990018.

VII. **SUMMARY OF CLINICAL STUDIES**

> **Primary** **Safety and Efficacy Study**
>
> **Objective**
>
> The objective of this study was to examine the safety and efficacy of
> the Menicon Z^TM^ high Dk rigid gas permeable (RGP) lens material for
> continuous (extended) wear of up to 30 days/29 nights when compared to
> a soft (hydrophilic) contact (SCL) lens approved for continuous wear
> of up to 7 days/6 nights.

## Study Design

The study was designed as a prospective, multi-center, concurrent
cohort, controlled, open label clinical trial lasting 12 months after
the initiation of extended wear (EW). A total of 661 subjects were
enrolled at 24 investigational sites throughout the United States.
Subjects were not randomized by lens modality due to the differences
between RGP and SCL lenses; however, subjects were adapted daily wear
(DW) users in the selected lens modality, with no prior EW experience.
Subjects were assigned into either the Test lens (317 subjects/634 eyes)
or the Control lens (a 58% water Group IV ionic lens) (313 subjects/625
eyes). Lenses were worn bilaterally for the duration of the study.

for a minimum 2-week DW adaptation period, followed byses were cleaned
and disinfected ding this overnight removal. The Test lenses are d for
cause.

The Control cohort was comprised of adapted DW soft (hydrophilic)
contact lens wearers who were advanced to up to 7 days of "continuous"
wear after enrollment, after a minimum 2 week daily wear adaptation
period with the Control lens. The Control lenses were worn based upon
the labeled indications for up to 7 days extended wear. The Control
lenses were scheduled for replacement on a weekly basis.

Eligibility Criteria

a)  Inclusion Criteria

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1.  At least 18 years of age.

2.  Refractive error between --20 and +12, with or without astigmatism
    (5.00 d) with acuity correctable to 20/25 in each eye.

3.  Must be a successful daily wear soft or RGP contact lens wearer with
    no extended wear experience.

4.  In good general health.

5.  Willing and able to follow all instructions and keep appointments.

6.  Must understand and sign the Informed Consent.

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b)  Exclusion Criteria

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1.  Presence of ocular or systemic allergies or disease which required
    removal of contact lenses more than twice a day.

2.  Use of medications that had previously required discontinuation or
    limitation of contact lens wear.

3.  Refractive correction that does not fall within the available
    parameters.

4.  Functionally monocular subjects.

5.  History of corneal trauma or ocular surgery (except cataract surgery
    with implant).

6.  Clinically significant slit-lamp findings.

7.  Ocular infection or history of corneal hypoesthesia.

8.  Aphakia, keratoconus, or irregular cornea.

9.  Inability to insert, remove, and handle contact lenses.

10. Pregnancy or lactation.

11. Infectious or immunosuppresive disease.

12. Diabetes.

13. Participation in any other clinical study within the past 30 days.

Lens Care Systems

The Test subjects were allowed to use the Claris® Care System or the
Optimum System by LoBob® and were required to use Allergan ProFree/GP
Weekly Enzymatic Cleaner on a monthly basis.

The Control subjects could use one of the following care systems, ReNu®
Multi-Purpose Solution, Opti-Free® Express® Multi-Purpose Disinfecting
Solution, AOSept® Disinfectant, or the QUICK CARE™ System. The protocol
allowed for any soft contact lens approved rewetting solution to be used
by the Control subjects.

Lens Wearing Directions and Evaluations

No standards exist for a break in wearing time, without it being counted
as a break in extended wear. For this study, an appropriate extended or
continuous wear time was defined as an extended wear period, without a
break in wear time of greater than or equal to 6 hours.

All subjects underwent standardized ophthalmic examinations at
enrollment and at the specified follow-up examinations. The subjects
were also examined at unscheduled visits during the study period.

The examinations included the review and recording of subjective
symptoms and objective findings along with visual acuity (VA),
keratometry measurements, over-refraction and manifest refraction. The
lenses were examined for defects, damage and cleanliness and the results
of these examinations were recorded.

## Safety and Effectiveness Endpoints {#safety-and-effectiveness-endpoints .Style1}

The primary safety endpoint analysis was focused on a comparison of the
proportion of eyes with "threshold significant adverse events", which
included the proportion of eyes with significant VA changes and slit
lamp findings of corneal infiltrates, corneal staining, corneal edema,
palpebral conjunctival findings and corneal neovascularization
[\>]{.underline} grade 3. For the primary safety endpoints**,** the Type
I error (two-sided) is 5% and the Type II error is 20%.

Additional safety evaluations included the comparison of:

-   Percentage of discontinuations and reasons for discontinuation

-   Frequency and severity of reported adverse events

-   Frequency and severity of subjective symptoms, problems or
    complaints

-   Frequency and severity of positive slit lamp findings

-   Proportion of eyes with changes in keratometry measurements greater
    than 1.0 diopter in any meridian

-   Proportion of eyes with changes in refraction measurements greater
    than 1.0 diopter

-   Proportion of eyes for which the final lens visual acuity differs
    from the initial best corrected visual acuity by two Snellen lines
    or greater

The evaluation of efficacy was based upon:

-   The proportion of subjects in each cohort achieving and maintaining
    the targeted extended wear schedule

-   An assessment of subject reported visual function for all subjects
    completing at least 6 months related to refractive error as reported
    using the Refractive Status and Vision Profile (RSVP) questionnaire.

Subjects were eligible for study participation if they were at least 18
years of age, had signed an Informed Consent form, and complied with the
protocol-specified inclusion and exclusion criteria.

## Subject Assessments {#subject-assessments .Style1}

Subject examinations were scheduled to provide a two week daily wear
period to allow the subjects to adapt to the lenses assigned for the
study. At the 2-Week daily wear visit, the investigator either allowed
the subject to start extended wear following the schedule appropriate
for the assigned cohort, or discontinued the subject.

Extended wear follow-up visits were planned for 1 week, and 1, 3, 9, and
12 months after starting extended wear. The investigator also had the
option of examining subjects at a 24-72 hour visit after the initiation
of extended wear. Any other visits for any reason were recorded as
unscheduled visits.

Adverse events were defined in the protocol as any hazardous, sight
threatening condition such as: corneal ulcers, severe corneal abrasions
\>2mm in diameter, iritis, other ocular infections or inflammations,
corneal scarring or permanent loss of vision. In addition, any adverse
experience could be reported as an adverse event. Adverse events were
additionally categorized as Serious Adverse Events, Significant Adverse
Events, and Non-significant Adverse Events according to their severity.

Reasons for subject discontinuations included: subject or investigator
decision; protocol deviations, lost to follow-up, comfort, positive slit
lamp findings or adverse events, or unacceptable acuity. A completed
subject is defined as completing the 12 month extended wear period of
the study.

## Demographic Data {#demographic-data .Style1}

The Test and Control cohorts were comparable with regard to gender,
presence or absence of allergies, use of concurrent medications, and
proportion of smokers. The two cohorts were significantly different in
mean age, with the Test cohort older by an average of six years. In the
Test cohort, the mean age was 40.9 years, with a range of 18 to 70
years. In the Control cohort, the mean age was 34.5 years, with a range
of 18 to 65 years. This difference was expected due to the difference in
rigid gas permeable and soft lens material modalities.

Refractive error ranged from +8.00 to --19.00 diopters for the Test
cohort, with a mean of --4.42 diopters. Refractive error ranged from
+7.00 to --10.25 diopters for the Control cohort, with a mean of --3.35
diopters. All subjects entered into the study were successful adapted
daily wear wearers of the lens material modality used in the study.

## Data Analysis and Results

The statistical comparison is performed to evaluate safety and efficacy
using the protocol-established variables outlined below:

## Primary Safety Outcomes {#primary-safety-outcomes .Style2}

There are two types of safety criteria, visual acuity (VA) changes and
slit lamp findings. The VA criteria are a reduction in best corrected
visual acuity (BCVA) in either eye of two or more Snellen lines from the
dispensing BCVA, or a decrease in BCVA to below 20/40, whichever BCVA is
less. Both scheduled and unscheduled visits were included in the
analysis of whether a subject met the VA criteria. Safety determinations
are based upon a comparison between the Test and Control cohorts.

## Best Corrected Visual Acuity Changes:  {#best-corrected-visual-acuity-changes .Style2}

Only o ne Test completed subject met the reduction in BCVA criteria in
the right eye only. The vision was reduced from 20/15 at the EW 3 month
visit to 20/50 at the EW 6 month visit, but at two later scheduled
visits, the VA was 20/20 and then 20/15.

a.  Slit Lamp Observations

> The analysis of the safety criteria is also based on the following
> five slit lamp observations, corresponding with the original analysis
> variables that were not seen at the dispensing visit, but were seen in
> either eye at any scheduled or unscheduled visit.
>
> 1\. Infiltrates of grade 3 or 4: (infiltrates of sufficient concern to
> warrant temporary or permanent discontinuation from lens wear).
>
> 2\. Corneal Staining of grade 3 or 4
>
> 3\. Stromal edema of grade 3 or 4: (Signs or symptoms of edema
> persisting beyond 2 hours from awakening &/or causing disrupted vision
> or with other signs.)
>
> 4\. Palpebral Conjunctiva of grade 3 or 4: (Papillary response or
> hyperemia sufficient to warrant temporary or permanent discontinuation
> of wear.)
>
> 5\. Corneal neovascularization of grade 3 or 4: (Vessel penetration
> \>1.5 mm in a single quadrant, or \>1 mm in multiple quadrants.)

#######  {#section-1 .unnumbered}

#######  {#section-2 .unnumbered}

#######  {#section-3 .unnumbered}

#######  {#section-4 .unnumbered}

#######  {#section-5 .unnumbered}

#######  {#section-6 .unnumbered}

#######  {#section-7 .unnumbered}

####### 

##  {#section-9 .Style2}

##  {#section-10 .Style2}

##  {#section-11 .Style2}

##  {#section-12 .Style2}

##  {#section-13 .Style2}

####### Table 1 gives the number of subjects who met the above criteria at any of the visits. There were a total of 16 (5.1% of subjects initially enrolled) subjects in the Control group, and 20 (6.3%) in the Test group that met these criteria in either eye on any visit (scheduled or unscheduled). These percentages were not statistically significantly different from each other (p=0.50). The probability of such an event was unrelated to the subject's age. While subjects in the Test group were older than those in the Control group, there was no difference in age between those with and without these slit lamp defects.  {#table-1-gives-the-number-of-subjects-who-met-the-above-criteria-at-any-of-the-visits.-there-were-a-total-of-16-5.1-of-subjects-initially-enrolled-subjects-in-the-control-group-and-20-6.3-in-the-test-group-that-met-these-criteria-in-either-eye-on-any-visit-scheduled-or-unscheduled.-these-percentages-were-not-statistically-significantly-different-from-each-other-p0.50.-the-probability-of-such-an-event-was-unrelated-to-the-subjects-age.-while-subjects-in-the-test-group-were-older-than-those-in-the-control-group-there-was-no-difference-in-age-between-those-with-and-without-these-slit-lamp-defects. .unnumbered}

> TABLE 1
>
> Threshold Significant Slit Lamp Events
>
> [Visit Control Test]{.underline}
>
> 2 wk DW 1 1
>
> 24-72 hr EW 1 2
>
> 1 wk EW 2 3
>
> 1 month 1 2
>
> 3 months 2 4
>
> 6 months 3 2
>
> 9 months 3 3
>
> 12 months 1 0
>
> Unscheduled 8 11
>
> [Control]{.underline} [Test]{.underline}
>
> Total defects (OU counted as 1) 22 (10.8^\#^) 28 (11.8^\#^) p=0.75\*\*
>
> Total follow-up visits 2039 2372
>
> Defect at scheduled follow-up visits 14 (7.4\*) 17 (8.3\*) p=0.78\*\*
>
> Total scheduled follow-up visits 1888 2050
>
> Subjects with defects 16 (5.1%) 20 (6.3%) ^2^ = 0.44, p=0.50
>
> Subjects dispensed lenses 313 315
>
> \# defects in either eye per 1,000 visits
>
> \* defects in either eye per 1,000 scheduled visits
>
> \*\* Using Generalized Estimating Equations

There were 2039 total visits in the Control group and 2372 total visits
in the Test group. This resulted in an event rate (event in either eye)
of 10.8 per 1,000 subject visits (22/2039) in the Control group versus
11.8 per 1,000 subject visits (28/2372) in the Test group. This
difference was not statistically significant (p=0.75). For scheduled
visits alone, the rate is 7.4 per 1,000 scheduled visits in the Control
group and 8.3 per 1,000 scheduled visits in the Test group (p=0.78).

To examine whether the contact lens wearing time was related to the
likelihood of developing a slit lamp defect, average wearing time, in
days, reported on the scheduled visit prior to which the slit lamp
defect occurred was used. For those without any such defects, the
wearing time reported at the 3 month extended wear visit was used. This
was done because subjects had established their wearing patterns by this
time. The average wearing time among Controls was 6.5 and 6.0 days for
those without and with a slit lamp defect, respectively. Among the Test
group, the mean wearing time was 21.0 days in those without a slit lamp
defect, and 16.5 days among those who developed a defect. The
interaction between wearing time and development of a slit lamp defect
was not statistically significant (p=0.19).

There were no statistically significant differences in overall slit lamp
findings by group. Figure 1 shows that there was no significant
difference in time to first slit lamp defect by treatment group (Log
rank p value=0.71).

> FIGURE 1
>
> ![](media/image1.wmf){width="5.501388888888889in" height="4.0in"}
>
> Log Rank Test ^2^ = 18.33 p \< 0.0001
>
> Relative Hazard = 0.50 (95%CI: 0.36, 0.69)
>
> Top line is Test
>
> Bottom line is Control
>
> There were no statistical differences in the rates of the type
> specific findings by treatment group calculated as percent of subjects
> with any event type, except for 8 (2.5%) subjects with 3&9 o'clock
> corneal staining in the Treatment group compared with none in the
> Control group (p=0.007). The rate of binocular events was similar in
> the Test (1.3%) and the Control group (2.2%) (p=0.35).

##  {#section-14 .Style2 .unnumbered}

## Adverse events  {#adverse-events .Style2}

Adverse Events reported by the investigators are shown in Table 2. The
columns headed "Subjects" present the number of subjects with a specific
AE as a proportion of the total subjects in each cohort.

> **TABLE 2**
>
> **Adverse Events by Type**
>
> **All Test and Control Subjects**
>
> **[CORNEAL ADVERSE EVENTS]{.underline}** **[Subjects]{.underline}**
>
> **Inflammatory/Infectious Events [Test]{.underline}
> [Control]{.underline}**
>
> Infiltrative Keratitis 0.3% 2.6%
>
> Vascularized Limbal Keratitis 0.6% 0.0%
>
> Corneal Ulcers 0.3% 0.3%
>
> **Abrasions**
>
> Foreign Body 2.8% 0.3%
>
> Metabolic 0.0% 0.3%
>
> Unknown 0.0% 0.6%
>
> Chemical 0.3% 0.3%
>
> **Edema**
>
> Microcystic 0.0% 0.3%
>
> **[CONJUNCTIVAL ADVERSE EVENTS]{.underline}**
>
> Bacterial 0.6% 2.9%
>
> Viral 0.3% 0.0%
>
> Allergic 1.3% 0.6%
>
> GPC 0.3% 0.6%
>
> Unknown 0.3% 0.6%
>
> **[MISCELLANEOUS ADVERSE EVENTS]{.underline}**
>
> Sinus Infection 0.0% 0.3%
>
> Trauma 0.0% 0.3%
>
> Lens Displacement 0.0% 0.3%
>
> Neurological 0.0% 0.3%
>
> Episcleritis 0.3% 0.3%
>
> Lacrimal Occlusion 0.3% 0.0%
>
> Lens Awareness 0.3% 0.0%
>
> **Total Subjects 317 313**
>
> Figure 2 shows the time to the first adverse event for each subject in
> the study. There were a total of 63 events (36 in Controls and 27 in
> the Test group) in 59 subjects (33 in Controls and 26 in the Test
> group). Of the 59 subjects with these adverse events, one subject in
> the Control group has 3 separate events, one subject in the Control
> group had two separate events, and one subject in the Test group had
> two separate events. The differences in rates of these events were not
> different between treatment and Control groups.
>
> FIGURE 2
>
> ![](media/image2.wmf){width="5.501388888888889in" height="4.0in"}
>
> Log Rank Test: ^2^ = 0.14 p =0.71
>
> Relative Hazard = 1.13 (95%CI: 0.59, 2.19)
>
> Top line is Control
>
> Bottom line is Test
>
> The events were classified into serious, significant and not
> significant. There were no "serious" events in either group. There was
> not a statistically significantly different rate of "significant
> events" among the Test group compared with the Control groups (8.2%
> versus 10.5%, respectively, p=0.31). There was also no significant
> difference in the time to the first significant adverse event. (Log
> rank p-value=0.15).
>
> Events were classified by the clinicians as "definitely not related to
> the device", "unlikely related", "possibly related", "probably
> related", and "definitely related". There was a statistically
> significantly lower rate of adverse events considered "definitely
> related to the device" in the Test group compared with the Control
> group (none versus 2.2% respectively, Fisher's Exact two-sided
> p-value=0.007).

## Efficacy Outcomes {#efficacy-outcomes .Style2}

##   {#section-15 .Style2}

##  {#section-16 .Style2}

## Lens Wearing Time {#lens-wearing-time .Style2-c}

Table 3 contains the means, standard deviations, medians and maximum of
the reported average days wearing of contact lenses at each scheduled
visit. As per protocol, there are significant differences in wearing
time between the Control and Test groups at all visits (even at the one
week extended wear visit). At the 1week extended wear visit, the median
wearing time is 7 days for both groups, but by 1 month, the Test group
has a median wearing time of 21 days, which increases to 28 days at 3
months and 29 to 30 days thereafter, while the Control group remains at
7 days.

> TABLE 3
>
> Subject reports of average days of contact lens wear at scheduled
> visits
>
> [EW 1-Wk EW 1-Mo EW 3-Mo EW 6-Mo EW 9-Mo EW 12-Mo]{.underline}

#### Controls {#controls .unnumbered}

> Mean (SD) 5.9 (1.8) 6.4 (1.5) 6.5 (3.7) 6.5 (1.1) 6.7 (1.9) 6.5 (1.0)
>
> Median (Max) 7.0 (10) 7.0 (14) 7.0 (60) 7.0 (14) 7.0 (30) 7.0 (7)

#### Test {#test .unnumbered}

> Mean (SD) 6.3 (2.0) 18.6 (10.9) 20.9 (11.7) 23.9 (13.3) 24.0 (9.2)
> 23.8 (9.4)
>
> Median (Max) 7.0 (13) 21.0 (35) 28.0 (90) 29.0 (171) 29.0 (30) 30.0
> (30.)
>
> All mean wearing times for Control and Test groups are statistically
> significantly different.

Table 4 gives the proportion wearing the lenses as per schedule (for
example, at 12 months, 95.2% of Controls are wearing the lenses on
average between 6 and 8 days, and 67.8% of the Test group are wearing
the lenses an average of 28-30 days). In general, the compliance with
lens wear as recommended is quite good, although there is some fraction
of those in the Test group who are wearing lenses on a weekly schedule,
rather than monthly (12.8% at the 12 month follow-up are between 6-8
days on average).

> TABLE 4
>
> Distribution of average days of wear at scheduled visits
>
> [EW 1-Wk EW 1-Mo EW 3-Mo EW 6-Mo EW 9-Mo EW 12-Mo]{.underline}
>
> [Control]{.underline}
>
> \< 6 63 (22.3) 31 (11.5) 30 (11.8) 15 (6.3) 12 (5.5) 10 (4.8)
>
> 6-8 215 (76.0) 236 (87.7) 222 (87.4) 220 (92.8) 205 (93.6) 200 (95.2)
>
> 9-27 5 (1.8) 2 (0.7) 1 (0.4) 2 (0.8) 1 (0.5) 0
>
> 28-30 0 0 0 0 1 (0.5) 0
>
> 30+ 0 0 1 (0.4) 0 0 0
>
> Total 283 269 254 237 219 210
>
> [Test]{.underline}
>
> \< 6 59 (20.3) 37 (13.0) 23 (8.2) 12 (4.6) 13 (5.1) 10 (3.9)
>
> 6-8 215 (74.1) 53 (18.6) 54 (19.4) 36 (13.6) 25 (9.8) 34 (13.2)
>
> 9-27 16 (5.5) 75 (26.3) 60 (21.5) 51 (19.3) 44 (17.2) 40 (15.5)
>
> 28-30 0 114 (40.0) 135 (48.4) 162 (61.4) 174 (68.0) 174 (67.4)
>
> 30+ 0 6 (2.1) 7 (2.5) 3 (1.1) 0 0
>
> Total 290 285 279 264 256 258

The distribution of the visit reported wearing times over all extended
wear visits after 1 month is presented in Table 5 below.

Table 5

Average Lens Wearing Time

Reported after the 1 Month Visit

Completed Subjects

Wearing Time

[(in Days)]{.underline} [Test]{.underline} [Control]{.underline}

0-7 18.0% 99.4%

8-14 8.3% 0.4%

15-21 7.2% 0.0%

[\>]{.underline}22 66.5% 0.2%

A total of 82.0% of the completed Test subjects reported extended
wearing times at scheduled visits after 1 month that exceeded 7 days of
wear. Of these, the majority of the completed Test subjects (66.5%)
reported wearing times of greater than 21 days.

The distribution of the days of wear from subject diaries is presented
in Table 6 below:

Table 6

Extended Wearing Time

By Subject Diary

Completed Eyes

Wearing Time

[(Consecutive Days)]{.underline} [Test]{.underline}
[Control]{.underline}

0 to 7 Days 11.7% 73.1%

8 to 14 Days 9.8% 11.7%

15 to 21 Days 8.3% 2.2%

[\>]{.underline}22 Days 70.2% 13.0%

The results indicate that the proportion of the total wearing days of 22
days or greater is 70.2% for the completed Test eyes. This result
compares well with the visit reported average wearing times where 66.5%
of the average wear reported was for periods of 22 consecutive days or
greater.

## Quality of Life Evaluation (RSVP)  {#quality-of-life-evaluation-rsvp .Style2-c}

> The comparison of baseline to final responses on the Refractive Status
> and Vision Profile (RSVP) questionnaire was the second of the efficacy
> measures discussed in the protocol. The RSVP was designed to provide
> an evaluation of subject satisfaction with their vision and vision
> correction. The results of this evaluation indicated modest
> improvements in vision-related function and symptoms. Both Test and
> Control Cohorts reported some improvement satisfaction in going from
> daily to extended wear.

## Additional Safety Endpoints {#additional-safety-endpoints .Style2}

## Discontinuations {#discontinuations .Style1}

Over the duration of the study, 59 of the 317 Test cohort subjects
(18.6%) and 103 of the Control cohort subjects (32.9%) were discontinued
from the study. The Control cohort subjects had a higher discontinuation
rate due to Protocol Violations and Lost to Follow-up.

Three (3) Test and 9 Control cohort subjects were discontinued for
Positive Slit Lamp Findings. The 3 Test cohort subjects were
discontinued for limbal desiccation (1 subject), increased
neovascularization and 3&9 staining (1 subject), and raised epithelial
hypertrophy at the sites of old 3&9 scars (1 subject). The 9 Control
cohort subjects were discontinued for neovascularization (2 subjects),
GPC (2 subjects), mild microcysts and trace edema (1 subject), mild
microcysts and mild staining (1 subject), mild infiltrates, non-staining
and asymptomatic (1 subject), trace palpebral conjunctival findings (1
subject), and mild infiltrative keratitis (1 subject).

Three (3) Test and 7 Control cohort subjects were discontinued for
Adverse Events. The 3 Test subjects were discontinued for an epithelial
corneal defect (1 subject), solution sensitivity (1 subject), and
marginal ulcerative keratitis (1 subject). The 7 Control cohort subjects
discontinued for Adverse Event were discontinued for: severe epithelial
microcysts (1 subject), keratitis from contact lens overwear (1
subject), bacterial conjunctivitis (1 subject), sector field defect (1
subject), peripheral corneal ulcer (1 subject), focal infiltrative
keratitis (1 subject), and marginal infiltrative keratitis (1 subject).

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------

TABLE 7

Reasons for Discontinuation By Cohort

[Test Subjects]{.underline} [Control Subjects]{.underline}

Subjects Enrolled 317 313

Lost to Follow-up 12 3.8% 29 9.3%

Protocol Violation 9 2.8% 21 6.7%

Comfort 12 3.8% 16 5.1%

Subject Decision 13 4.1% 11 3.5%

Positive Slit Lamp Findings:

Related to Study Lens 3 0.9% 8 2.6%

Unrelated to Study Lens 0 0% 1 0.3%

Adverse Event 3 0.9% 7 2.2%

Investigator Decision 4 1.3% 4 1.3%

Unacceptable Visual Acuity 0 0% 1 0.3%

Study Product Not Dispensed 0 0% 0 0%

Other: 3 0.9% 5 1.6%

Total Subjects Discontinued 59 18.6% 103 32.9%

##  {#section-17 .Style1 .unnumbered}

## Slit Lamp Findings {#slit-lamp-findings .Style1}

Table 8 presents the percentage and average severity of positive
findings by category throughout the extended wear phase of the study for
all eyes.

> Table 8
>
> Incidence and Average Severity of Positive Slit Lamp Findings
>
> Completed and Discontinued Eyes Pooled
>
> [Test Cohort]{.underline} [Control Cohort]{.underline}
>
> [Finding]{.underline} [EW Total]{.underline} [EW Total]{.underline}
>
> Sample Size 3901 3405
>
> [Incidence]{.underline} [Average]{.underline} [Incidence]{.underline}
> [Average]{.underline}
>
> [Severity]{.underline} [Severity]{.underline}
>
> Epithelial Edema 1.1% 1.3 3.6% 1.1
>
> Epithelial Microcysts 1.6% 1.0 7.0% 1.3
>
> Stromal Edema 0.3% 1.3 1.1% 1.3
>
> Corneal Neovascularization 7.4% 1.1 14.5% 1.1
>
> Corneal Staining 12.4% 1.2 17.4% 1.2
>
> 3&9 Corneal Staining 22.2% 1.2 0.4% 1.5
>
> Limbal & Bulbar Hyperemia 13.2% 1.2 15.4% 1.2
>
> Palpebral Conjunctiva 8.1% 1.3 22.5% 1.3
>
> Infiltrates 0.2% 2.1 0.8% 1.7
>
> Other: 6.4% 6.7%

For the extended wear phase of the study, for all visits and all eyes,
0.1% of the Test cohort and 0.2% of the Control cohort slit lamp
findings were rated as Grade 3 or greater (moderate or severe). The
distribution of moderate or severe positive slit lamp findings as a
proportion of the eyes in each cohort is presented in Table 9.

> Table 9
>
> Distribution of Moderate & Severe Positive Slit Lamp Findings
>
> Incidence By Cohort
>
> All Completed and Discontinued Eyes Pooled
>
> [Grade 3-Moderate]{.underline} [Grade 4-Severe]{.underline}
>
> Test Control Test Control
>
> Sample Size 634 625 634 625
>
> Epithelial Edema 0.0% 0.5% 0.0% 0.0%
>
> Epithelial Microcysts 0.0% 1.4% 0.0% 0.3%
>
> Corneal Staining 1.6% 0.3% 0.0% 0.6%
>
> 3&9 O'clock Staining 2.1% 0.0% 0.0% 0.0%
>
> Limbal & Bulbar Hyperemia 1.9% 1.0% 0.0% 1.4%
>
> Palpebral Conjunctiva 1.4% 3.2% 0.0% 0.3%
>
> Infiltrates 0.6% 0.3% 0.0% 0.0%
>
> Slit Lamp Other 0.9% 0.3% 0.0% 0.5%

##  {#section-18 .Style1 .unnumbered}

## Symptoms, Problems and Complaints {#symptoms-problems-and-complaints .Style1}

Except for Lens Needs Cleaning and "other", the symptoms, problems and
complaints reported during the study were similar in incidence between
the Test and Control cohorts during the extended wear phase of the
study.

Lens needs cleaning was reported at 11.5% of all examinations for the
Test cohort as compared to 4.9% for the Control cohort. This is expected
since the Control lenses were discarded every 7 days while the Test
lenses are durable lenses and were replaced during the study at a rate
of 1 lens per subject per year.

Other symptoms were reported at 11.2% of all extended wear examinations
for the Test cohort and at 15.1% of all extended wear visits for the
Control cohort and were primarily Dryness.

## Keratometric and Refractive Changes {#keratometric-and-refractive-changes .Style1}

A total of 104 (8.5%) Test cohort eyes and 55 (4.7%) Control cohort eyes
had keratometry measurements change by more than 1.00 diopter. The
maximum change was 3.50 diopters with the Test lens and 2.63 diopters
with the Control lens. The reasons for the changes as reported by the
investigators were: changes related to extended wear, differences
between exam rooms or observers, normal corneal changes, or corneal
molding/sphericalization of the cornea.

A total of 70 (5.7%) Test cohort eyes and 10 (0.9%) Control cohort eyes
had a refractive error change greater than 1.00 diopter. The maximum
change was 3.50 diopters with the Test lens and 2.63 diopters with the
Control lens. The reasons for the changes as reported by the
investigators were primarily lens induced corneal flattening, operator
or instrument error, and the creation or recovery from corneal edema.
These findings indicate that neither the Control or the Test contact
lens caused any adverse changes in corneal shape.

The reasons cited by the investigators for changes in refraction for the
Test cohort were: changes due to continuous wear versus daily wear,
normal changes, changes from going to higher Dk lenses, and corneal
molding with RGP wear. For the Control cohort, the reasons cited
included: normal changes, probable edema undetectable by slit lamp, and
1 subject had refractive surgery performed 1 month prior to exit (exited
for protocol non-compliance).

## Visual Acuity {#visual-acuity .Style1}

Best corrected visual acuities recorded at the initial visit were
compared to the lens visual acuities at the final visit for all Test and
Control eyes and all VA decreases of 2 Snellen lines or greater were
identified. For the Test cohort there were 16 changes (2.5%) of 2 lines
or greater over the duration of the study and for the Control cohort
there were 20 changes (3.2%) of 2 lines or greater over the course of
the study.

Changes reported for the 16 Test eyes were explained by the
investigators as resulting from:

-   increased or progressive myopia (4 eyes);

-   normal VA fluctuation (5 eyes);

-   increase in cataract density (2 eyes from 1 subject);

-   lens coating/deposits (2 eyes);

-   due to dryness (1 eye);

-   lens power checking as weak (1 eye);

-   and unknown (1 eye).

    Changes reported for the 20 Control eyes were explained by the
    investigators as resulting from:

-   normal VA fluctuation (7 eyes);

-   increase in cylinder (3 eyes);

-   refraction change --0.25 sph/-0.50 cyl (2 eyes);

-   increase in corneal astigmatism (1 eye);

-   change in Rx (1 eye);

-   due to dry eyes (1 eye);

-   due to astigmatism (4 eyes);

-   monovision near eye (1 eye).

    The proportions and the reasons cited for the changes from the best
    corrected visual acuities to the lens visual acuities are similar
    between the Test and the Control cohort eyes.

    The proportion of eyes achieving lens visual acuities of 20/20 and
    20/30 were compared from the dispensing to the final exit visit for
    both the Test and the Control cohort eyes. These proportions are
    illustrated in Table 10 below:

    Table 10

    Proportion of Lens VA's

    [Eyes with Lens VA 20/30 or better]{.underline}:
    [Dispensing]{.underline} [Final Visit]{.underline}

    Completed Test Eyes 99.2% 99.6%

    Completed Control Eyes 100.0% 100.0%

    Discontinued Test Eyes 96.5% 95.3%

    Discontinued Control Eyes 99.0% 99.4%

    [Eyes with Lens VA 20/20 or better]{.underline}:
    [Dispensing]{.underline} [Final Visit]{.underline}

    Completed Test Eyes 88.8% 83.5%

    Completed Control Eyes 93.6% 83.8%

    Discontinued Test Eyes 82.5% 80.2%

    Discontinued Control Eyes 89.8% 77.6%

    The proportion of eyes achieving lens visual acuities of 20/20 and
    20/30 were similar between the Test and the Control eyes and support
    the efficacy of the study contact lenses.

##  {#section-19 .Style2}

##  {#section-20 .Style2}

a.  
b.  
c.  
d.  
e.  
f.  
g.  
h.  
i.  
j.  
k.  
l.  
m.  
n.  
o.  
p.  
q.  
r.  
s.  
t.  
u.  
v.  
w.  
x.  
y.  
z.  
a.  
b.  

##  {#section-21 .Style2}

## Lens Replacements {#lens-replacements .Style2}

Lens replacement rates are not comparable between the Test lenses and
the Control lenses due to the difference in lens materials used. The
Test lenses are a durable RGP lens, designed for continuous use over a
long period of time and replacement only for cause. The Control lenses
are planned replacement lenses that were replaced on a weekly basis. The
difference between the replacement schedules means that replacements of
the Control lenses could be subsumed in the planned replacement
schedule, whereas the Test lens replacements would only be for a
specific need.

Given this difference, the difference in the number of lenses replaced
for cause between the Test and the Control cohorts is expected. The Test
cohort replaced 348 lenses over the duration of the study (completed and
discontinued eyes pooled). This results in a replacement rate of
approximately 1 lens per subject per year.

The most frequently cited reasons for replacement for the Test cohort
were Other (32.8% - mostly Loss), Parameter (Rx) Changes (29.0%) and
Unacceptable VA (11.5%). The most frequent reasons cited for the 85
lenses replaced for the Control cohort were Parameter (Rx) Changes
(55.3%) and Unacceptable VA (21.2%).

**Corneal and Endothelial Evaluation**

Two of the sites recruited for the clinical study performed a corneal
and endothelial evaluation. Corneal thickness was measured to compare
corneal swelling resulting from edema. Corneal thickness was measured at
OSU with the Cornea-gage II (Sonogage, Cleveland, OH) ultrasonic
pachometer and at CWRU with the CompuScan (Storz, St. Louis, MO)
pachometer. Measurements were done on the right eye at the Dispensing
visit, the 2 Week Daily Wear visit, and the 1 Week, 6 Month and 12 month
Extended Wear visits. The average of six ultrasonic pachometry
measurements was recorded at each of these visits. Diurnal fluctuation
in corneal thickness was controlled for by scheduling follow-up visits
at the approximate same time of day as the baseline visit.

Both the Ohio State University and Case Western Reserve University sites
used the Konan NonContact Robo specular microscope for endothelial
evaluations. These microscopes were calibrated by the manufacturer and
calibration was monitored before, during and after the study by the
investigators. The subject was instructed to watch the fixation light in
primary gaze and an image was captured from the central corneal
endothelium of both eyes. After image capture, the data was stored and
later, all contiguous cells with visible borders were dotted in the
center by the same examiner. A minimum of 100 cells per eye was dotted
for each subject. Endothelial cell analysis was automatically performed
by the endothelial camera software and the cell density, coefficient of
variation (CV) (standard deviation of cell area/mean cell area) and
percentage of six-sidedness was recorded for each eye.

The study of the central corneal thickness evaluated whether there was a
difference in corneal thickness change in subjects who wore the control
soft contact lens for 7 day/6 night extended wear and subjects who wore
the Test RGP lenses for 30 day/29 night extended wear in a controlled
clinical trial. The results of the study demonstrated a significant
(p=0.03) increase in corneal thickness in the Control lens cohort as
compared to the Test lens cohort. This observation is due to the higher
level of oxygen permeability with the Test RGP lenses.

The endothelial evaluation looked at the density and six-sidedness of
the endothelial cells over the duration of the controlled study. The
final conclusion of this evaluation was that the Test lens wearers in
this study did not have significant endothelial cell morphology changes
after one year of nearly continuous contact lens wear.

VIII. **CONCLUSIONS DRAWN FROM THE STUDIES**

> The results of the preclinical and clinical studies provide reasonable
> assurance of the safety and efficacy of the Menicon Z^TM^ RGP lens for
> the subject population, refractive conditions and specified duration
> of wear. The clinical endpoints measured in this study for the Menicon
> Z^TM^ RGP lens for continuous (extended) wear of up to 30 days/29
> nights are comparable to a soft (hydrophilic) contact lens for
> continuous wear of up to 7 days/6 nights. Although the potential
> exists for minor differences in physiological response by gender for
> the target population, minimal number of clinically significant
> differences are of clinical importance for this device. Therefore, FDA
> has concluded that the subject lenses are safe and effective when worn
> in accordance with the approved labeling.

IX. **PANEL RECOMMENDATION**

> In accordance with the provisions of section 515(c)(2) of the act as
> amended by the Safe Medical Devices Act of 1990, this PMA was not
> referred to the Ophthalmic Devices Panel, an FDA advisory committee,
> for review and recommendation because the information in the PMA
> substantially duplicates information previously reviewed by this
> panel. However, homework assignments were made individually to three
> panel members in order to confirm the conclusions from the internal
> FDA clinical review. The panel reviews did not raise any additional
> clinical issues that were unique to this device or different from
> those identified in the internal review. All three panel members
> recommended approval of the device for extended wear up to 30 days.

X.  **CDRH DECISION**

> FDA issued an approval order on \_\_\_\_\_\_\_\_\_\_\_\_

XI. 

XII. **XIV.** **APPROVAL SPECIFICATIONS**

Directions for use: See the labeling

Hazards to Health from Use of the Device: See the Indications,
Contraindications,

Warnings, Precautions and Adverse Events in the labeling.

Postapproval Requirements and Restrictions: See approval order.