PMA P030016 Specular Microscopy Substudy

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PMA P030016 Specular Microscopy Substudy

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Cardiovascular and Ophthalmic Team Leader, Division of Biostatistics ... Includes both initial operational loss and normal loss due to ageing ... – PowerPoint PPT presentation

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Title: PMA P030016 Specular Microscopy Substudy

1
PMA P030016 Specular Microscopy Sub-study

Gerry Gray, Ph.D.
Cardiovascular and Ophthalmic Team Leader,
Division of Biostatistics
Office of Surveillance and Biometrics
Center for Devices and Radiological Health
October 3, 2003

2
Specular microscopy sub-study design

Endothelial cell counts
Specular microscope photographs
Multiple images per eye
Images read at a core center (Emory)
Follow up
Original design 3 months, 1 and 2 years.
Study modified to add 3, 4 year visits.
Purpose investigate effects on endothelial cells
through time
306 eyes enrolled have at least one count

3
Eye accountability
4
Other combinations of visits
5
ECD results for all eyes and visits
6
Mean cell counts for various cohorts
7
Estimates of cell loss over duration of the study

Estimates are fairly stable regardless of method
of calculation
Range of estimates at 3 years 8.5 to 8.9
Approximately 225 235 cells/mm2
Includes both initial operational loss and normal
loss due to ageing
Range of estimates at 4 years 8.4 to 9.7
Approximately 220 260 cells/mm2

8
Steady state long term loss

Estimate depends largely on
Cohort that is used
Whether we use all the data or only the 3 4
year data
Sponsors analysis
Percent change between 3 4 years
Using only 3 4 year observations from cohort
with both 3 4 year visits
Recall from the previous Table that this
57-patient cohort has a relatively low 3-year
count.
Estimated percent change 0.07 (i.e. a slight
gain)
95 CI -1.44, 1.58
Other cohorts (e.g. BL, 2 visits) have
relatively higher 3-year count.
Various analyses using these cohorts produce a
loss of about 2 per year.

9
Test for change in slope

In all cohorts, the loss does appear to level
off after 3 years.
But theres no strong statistical evidence that
the leveling off is real (versus random chance
and/or a small 4-year sample).
Piecewise linear model
Initial (operative) loss from baseline to 3
months
Linear loss from 3 months to 3 years
Linear loss (possibly different slope) from 3
years to 4 years
Test for different 3-4 year slope p 0.37
Implication steady state loss should be
estimated using all data after 3 months.

10
Two different fits
11
Extrapolation from different fits
12
Extrapolation caveats

ALWAYS a questionable exercise to extrapolate
beyond the range of available data, especially to
the degree we want here.
Highly dependent on the model we use the
assumptions we make.
BOTH of the previous extrapolations assume that
loss will continue linearly for 30 years.
Probably much more important to think about
If its necessary to obtain good long-term data.
If so, how to go about it.

13
Phase IV study possibilities

Continuation of phase III study
Higher quality data
Fewer patients
More costly
Registry approach
Simpler cheaper
More patients
Less information (specular microscopy not
generally available)
Choice depends on goals

14
How do individual patients fare?

Perhaps more important than average cell loss
through time.
What proportion of patients will have major
operative loss?
What proportion of the patients will show cell
loss greater than some critical amount?

15
Regression on individual eyes
Piecewise linear fits to 206 individual eyes (BL,
2 cohort).
16
Regression on individual eyes

Mean baseline 2654 cells/mm2
Mean initial loss 204 cells/mm2/yr
(absolute loss 51 cells/mm2, or 1.9)
Mean rate after 3 months 53 cells/mm2/yr, or
2/yr
Tolerance interval for long term rate
95 confident that
60 of patients have a loss no worse than 82
cells/mm2yr (3.1)
90 of patients have a loss no worse than 163
cells/mm2/yr (6.1)
99 of patients have a loss no worse than 247
cells/mm2/yr (9.3)

17
Predictors of endothelial cell loss

There appear to be several statistically
significant predictors of endothelial cell loss
(baseline measurements)
This includes anterior chamber depth, MRSE,
diopter, ECD coefficient of variation
Dependent variable (annual loss) taken from
per-eye regression.
Using continuous measurements for covariates.
Sponsor presented analyses using binned data
(cut at 15.0D or at 7D 10D) that do not show
MRSE effect.
Age, gender, IOP, cylinder, axis, etc. did not
appear to be significant predictors of cell loss.

18
Clinically significant ACD effect?
Annual cell loss estimated using per-eye
regressions.
19
Sponsors ACD summary
Estimates are percent loss relative to index
group.
20
Questions for panel
21
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