Transcript Document 7470880

Statistical Issues for PMA P050034
Implantable Miniature Telescope
(IMT)
T.C. Lu and Yao Huang
Cardiovascular and Ophthalmic Branch
Division of Biostatistics
Office of Surveillance and Biometrics
Center for Devices and Radiological Health
July 14, 2006
1
Major Issue
• To investigate the effects of device on
Endothelial Cell Density (ECD) over time.
– Analyses are based on 24-month follow-up
data.
– Both IMT and fellow eye data are used.
2
ECD scatter-plots
4500
4500
IMT Eyes
4000
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
1000
500
500
0
0
-0.5
4.5
9.5
14.5
months
Fellow Eyes
4000
19.5
24.5
-0.5
4.5
9.5
14.5
months
19.5
3
24.5
Issues to be Discussed
1. Mean ECD loss over time
– Acute vs. chronic loss
2. Distribution of ECD loss over time
– proportion of patients with ECD loss > 10%, 50% for
IMT eyes and fellow eyes
3. Other clinical variables may affect ECD: ACD
and surgical order (surgeon experience)
4. Modeling of ECD data – how long would it take
for an IMT-implanted eye to reach ECD 1000 or
lower?
4
1. Mean ECD Percent Loss
(IMT eyes)
• Acute ECD loss associated with surgery
(baseline-3 months):
– Mean: 20%; 95% CI (17%, 23%)
• Chronic ECD loss associated with
continuous use of device (3-24 months):
– Mean: 9.7%; 95% CI: (6.3%, 13.0%) or
– Mean annual loss = 5.4%; 95% CI (2.0%,
8.8%)
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Mean ECD Over Time
3000
2500
2000
1500
1000
500
IMT eyes
0
-0.5
4.5
9.5
months
14.5
19.5
6
24.5
Mean ECD Over Time
3000
2500
2000
1500
1000
500
IMT eyes
Fellow eyes
0
-0.5
4.5
9.5
months
14.5
19.5
7
24.5
ECD loss > 10%
2. % of Eyes with ECD Loss >10%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
IMT eyes
Fellow eyes
3 mth
12 mth
18 mth
24 mth
8
ECD loss > 50%
% of Eyes with ECD Loss >50%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
IMT eyes
Fellow eyes
3 mth
12 mth
18 mth
24 mth
9
ECD % Change for IMT eyes
Percentiles
Time
(month)
<5%
< 10 %
< 20 %
< 50 %
0-3
-67%
-52%
-37%
-14%
3-24
-35%
-27%
-19%
-8%
0-24
-75%
-59%
-43%
-24%
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3. Other Clinical Factors that May
Affect ECD
• Anterior Chamber Depth (ACD)
– Mean = 3.147mm (IMT eyes)
– S.D. = 0.380mm
– Range = (2.48mm, 4.74mm)
• Surgical order (<3rd case, >4th case)
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Sponsor’s Results
• ACD has a linear effect (p<0.05) on ECD
% change from baseline to 3 months, but
not from 3 months to 24 months.
• Surgical orders (surgeon experiences) did
not show statistically significant
difference.
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4. The Modeling Results
of the ECD data
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ECD data by patients
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A Mixed Effect Model
3000
2500
2000
1500
1000
IMT eyes
95% CL for IMT
500
Fellow eyes
95% CL for Fellow
0
0
5
10
months
15
20
15
25
Model Fitting Results
Estimate
2466.89
Standard
Error
19.75
2-sided
p-value
< 0.0001
-169.81
14.28
< 0.0001
Chronic monthly
change for IMT
Eye
-9.83
1.38
< 0.0001
Acute monthly
change for
Fellow Eye
-6.59
4.61
0.1532
Chronic monthly
change for
Fellow Eye
-3.03
1.05
0.0039
Effect
Intercept
Acute monthly
change for IMT
Eye
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Comparison of Slopes
Comparison
2-sided p-value
Acute ECD slopes between IMT &
Fellow eyes (-169.81 vs. -6.59)
< 0.0001
Chronic ECD slopes between IMT
& Fellow eyes (-9.83 vs. -3.03)
< 0.0001
IMT eyes: acute slope vs. chronic
slope (-169.81 vs. -9.83)
< 0.0001
Fellow eyes: acute slope vs. chronic
slope (-6.59 vs. -3.03)
0.4863
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Caveats of Data Extrapolation
• Always a questionable exercise to
extrapolate beyond the range of available
data.
• Highly dependent on the model &
assumptions.
– Linear? Exponential? Other?
• Also should consider:
– If it is necessary to obtain good long-term
data.
– If so, how to go about it.
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Data Extrapolation to Year 4
4500
4500
IMT eyes
predicted mean ECD
ECD=1000
4000
4000
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
1000
500
500
0
0
-0.5
9.5
19.5
29.5
months
39.5
Fellow eyes
predicted mean ECD
ECD=1000
49.5
-0.5
9.5
19.5
months
29.5
39.519
49.5
Percentage of Eyes with Predicted
ECD≤1000
IMT eyes
Fellow eyes
2 years
24/216 (11.1%)
1/216 (0.5%)
3 years
38/216 (17.6%)
2/216 (0.9%)
4 years
49/216 (22.7%)
3/216 (1.4%)
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Baseline ECD Quartiles of
IMT Eyes
ECD
< Q1
1695.00 ~ 2261.33
Q1 ~ median
2261.33 ~ 2513.00
Median ~ Q3
2513.00 ~ 2772.17
> Q3
2772.17 ~ 3356.00
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Prediction of Eyes with ECD≤1000
at Year 2
IMT Eyes
Fellow Eyes
Baseline ECD < Q1
11/54 (20.4%)
1/54 (1.9%)
Baseline ECD in Q1 ~
median
4/54 (7.4%)
0
Baseline ECD in
Median ~ Q3
5/54 (9.3%)
0
Baseline ECD > Q3
4/54 (7.4%)
0
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Projection of Eyes with ECD≤1000
at Year 3
IMT Eyes
Fellow Eyes
Baseline ECD < Q1
17/54 (31.5%)
2/54 (3.7%)
Baseline ECD in Q1 ~
median
8/54 (14.8%)
0
Baseline ECD in
Median ~ Q3
9/54 (16.7%)
0
Baseline ECD > Q3
4/54 (7.4%)
0
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Projection of Eyes with ECD≤1000
at Year 4
IMT Eyes
Fellow Eyes
Baseline ECD < Q1
21/54 (38.9%)
2/54 (3.7%)
Baseline ECD in Q1 ~
median
12/54 (22.2%)
0
Baseline ECD in Median
~ Q3
11/54 (20.4%)
1/54 (1.9%)
Baseline ECD > Q3
5/54 (9.3%)
0
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Baseline Demographics
for IMT Eyes
Baseline ECD
Baseline ECD < Q1
1695.00 ~
2261.33
Age
(SD)
76.81
(6.75)
Baseline ECD in
Q1 ~ median
2261.33 ~
2513.00
2513.00 ~
2772.17
2772.17 ~
3356.00
75.97
(6.42)
76.01
(7.15)
75.44
(8.72)
Baseline ECD in
Median ~ Q3
Baseline ECD > Q3
ACD
(SD)
3.10
(0.38)
3.13
(0.38)
3.18
(0.40)
3.18
(0.37)
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The Sponsor’s Model
on ECD Data
• Three piecewise linear function with two
breakpoints at : t=3 and t=9 months
• Only data of IMT eyes used
• Results are consistent with those of the
Agency’s model for IMT eyes
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Results of Using Two Breakpoints
Effect
Estimate
Standard
Error
2-sided
p-value
Intercept
1798.53
206.20
<0.0001
Month (<3M)
-329.37
72.08
<0.0001
-17.63
3.38
<0.0001
-5.76
1.61
0.0004
180.55
64.42
0.0053
64.34
22.72
0.0048
Month (3 to
9M)
Month (>9M)
ACD
ACD*Month
(<3M)
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Predicted Probability of
ECD <1000 cells/mm2
at 4 Years by Sponsor
Baseline
ECD
ACD=2.5 ACD=3.0 ACD=3.5 ACD=4.0
2500
0.149
0.116
0.089
0.067
2000
0.398
0.341
0.288
0.238
1600
0.644
0.587
0.527
0.467
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Conclusions
• For the group of IMT-implanted eyes,
ECD decreases throughout the study.
• Slopes of acute and chronic periods are
both significantly different from zero.
• The chronic ECD loss can not be ignored.
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Conclusions (cont.)
• At both acute and chronic periods, the
slopes are significantly different between
the IMT eyes and fellow eyes, which
suggests that there is a significant
treatment (IMT implantation) effect in
ECD change.
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Question for Panel
Does the data presented provide
reasonable assurance of safety
in terms of ECD loss for this
device?
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