The OPHTEC ARTISANTM Myopia lens: endothelial cell counts

1. 1 The OPHTEC ARTISANTM Myopia lens: endothelial cell counts Gerry Gray, Ph.D. Cardiovascular and Ophthalmic Team Leader, Division of Biostatistics Office of Surveillance and Biometrics Center for Devices and Radiological Health February 5, 2004

2. 2 Study design Purpose: investigate effects of device on endothelial cells through time. Endothelial cell counts & measurements Specular microscope photographs Multiple images per eye (fall 2000 & later) Counts at: Baseline, 6 months, 1, 2, 3 years. Due to large variability, images were re-read 662 eyes originally enrolled & counted Variability was quite high 353 available photos from reliable machines were re-counted at one reading center NO CONTROL GROUP AVAILABLE

3. 3 ECD recount eye accountability

4. 4 Available recount data

5. 5 Available recount data

6. 6 ECD results for all eyes and visits

7. 7 Mean cell counts for various cohorts

8. 8 Estimates of cell loss over duration of the study Baseline to 3 years: 4.75% - 5% loss Using 107 BL:3yr patients, sponsor estimates 4.75% baseline to 3 year loss, 95% CI = [3.3%, 6.2%]. Summing sponsor�s % change by period: 5.05% baseline to 3 year loss, 95% CI = [3.1%, 7.0%] Includes both initial operational loss (if any) and normal loss due to ageing.

9. 9 �Steady state� long term loss What is the long term rate of change in endothelial cell density that we can expect to see? Estimate depends mostly on: If we believe there is any initial operative loss If we estimate using Difference between baseline & 3 years, or All visits (regression) Cohort that is used for estimation Whether we use all eyes, 2+FU, eyes w/all visits, etc.

10. 10 What are the �standards�? Want reasonable assurance that endothelial cell density is preserved. Normal ageing about 0.6% per year Consensus (?) points for concern: 1500 cells/mm^2, 800 cells/mm^2 ALL of the �standards� are written in terms of the upper confidence limit on the rate of loss. FDA draft guidance (& Ophthalmic panel) annual rate from 3 mo. � 3 yr., upper 90% CI 1.5% ISO, ANSI (not standards for acceptable rate of loss) calculate sample size using 2.0% upper 90% CI

11. 11 �Steady state� long term loss Percent change from baseline (NOT equivalent to steady state) 107 patients with baseline & 3 year counts Annual loss: 1.59%, 95% CI [1.1%, 2.1%], 2.0% one-sided limit 57 patients with counts at all time points (�consistent cohort�) Annual loss: 1.27%, 95% CI [0.4%, 2.1%], 2.0% one-sided limit Regression-based analyses using all time points produce a loss of 1.7% -2.0% per year Sponsor: 183 eyes w/ baseline count, including baseline, GEE Annual loss: 1.72%, 95% CI [1.23%, 2.22%] Alternate: 322 eyes w/2+FU, 6mo through 3yrs, not including baseline Annual loss: 1.9%, 95% CI [1.5%, 2.3%] Annual loss: 2.0%, 95% CI [1.6%, 2.5%] �depending on GEE model Additional 4-year data on 27 patients: 1.63% loss between 3 and 4 years

12. 12 Test for change in slope For eyes with baseline measurements, virtually no change between baseline and 6 months Piecewise linear model: Baseline to 6 months, 6 months to 3 years Various methods of testing do not show a significant change in slope Data do not indicate any peri-operative period with increased rate of endothelial cell loss Conflicts with expected outcomes in all guidance documents

13. 13 Long term loss Percent change from baseline is not equivalent to the �steady state� long term rate Regression-based methods use intermediate time points and should generally be considered superior to simple differences between start & end times Estimate depends somewhat on whether baseline count is included in regression 1.7% loss including baseline 1.9% - 2.0% not including baseline Upper CI limits 2.2% - 2.5% All regressions use GEE methods for within-patient correlation

14. 14 Results from three different fits

15. 15 Extrapolation from different fits

16. 16 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. ALL of the previous extrapolations assume that loss will continue linearly. Probably much more important to think about: If it�s necessary to obtain good long-term data. If so, how to go about it.

17. 17 How do individual patients fare? Perhaps more important than �average� cell loss through time. What proportion of the patients will show cell loss greater than some critical amount? What proportions of patients will have cell densities less than 1500, 800 cells/mm^2 in 10, 20, 30 years? Difficult to answer this with any confidence Extrapolation of percentiles

18. 18 Estimated outcomes for individual patients

19. 19 Summary of estimates from individual patient modeling

20. 20 Predictors of endothelial cell loss

21. 21 Question for panel Do the endothelial cell data presented provide reasonable assurance of safety of the Artisan myopia lens?

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