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PMA P030016 Specular Microscopy Sub-study

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. Specular microscopy sub-study design.

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PMA P030016 Specular Microscopy Sub-study

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  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/mm^2 • 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/mm^2

  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 • Sponsor’s 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 there’s 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 it’s 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/mm^2 • Mean initial loss = 204 cells/mm^2/yr (absolute loss 51 cells/mm^2, or 1.9%) • Mean rate after 3 months = 53 cells/mm^2/yr, or 2%/yr • Tolerance interval for long term rate: • 95% confident that • 60% of patients have a loss no worse than 82 cells/mm^2^yr (~3.1%) • 90% of patients have a loss no worse than 163 cells/mm^2/yr (~6.1%) • 99% of patients have a loss no worse than 247 cells/mm^2/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. Sponsor’s ACD summary Estimates are percent loss relative to index group.

  20. Questions for panel

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