PMA P030016 Specular Microscopy Substudy

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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

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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

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Eye accountability
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Other combinations of visits
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ECD results for all eyes and visits
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Mean cell counts for various cohorts
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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

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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.

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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.

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Two different fits
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Extrapolation from different fits
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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.

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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

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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?

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

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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.

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