1. 1 The OPHTEC ARTISAN TM 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.Purpose: investigate effects of device on endothelial cells through time. Endothelial cell counts & measurementsEndothelial 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-readDue to large variability, images were re-read –662 eyes originally enrolled & counted Variability was quite highVariability was quite high –353 available photos from reliable machines were re-counted at one reading center NO CONTROL GROUP AVAILABLENO CONTROL GROUP AVAILABLE

3. 3 ECD recount eye accountability No baseline visit 170 one subsequent one subsequent 9 two or more subsequent two or more subsequent161 Baseline, 0,1 subsequent 22 Baseline, 2,3 subsequent 104 All visits 57 two or more visits after baseline two or more visits after baseline322 TOTAL353 All eyes accountability based on ECD recount dataset submitted on 12/10/2003. Includes 215 first eyes and 138 fellow eyes

4. 4 Available recount data Green indicates an ECD count is present. Individual patients can be traced horizontally. Numbers of patients with ECD counts indicated for selected regions.

5. 5 Available recount data Green indicates an ECD count is present. Individual patients can be traced horizontally. Numbers of patients with ECD counts indicated for selected regions.

6. 6 ECD results for all eyes and visits Blue line connects mean counts at each time.

7. 7 Mean cell counts for various cohorts COHORT nBL 6 mo 1 yr 2 yr 3 yr All eyes 35327612768272026622578 w/o BL 170NA2779267226382552 w/ BL 18327612764275826882612 2+FU 32227672772271426632583 All visits 5728162811276627582691 2+FU = patients with two or more post-op visits.

8. 8 Estimates of cell loss over duration of the study Baseline to 3 years: 4.75% - 5% lossBaseline 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?What is the long term rate of change in endothelial cell density that we can expect to see? Estimate depends mostly on:Estimate depends mostly on: –If we believe there is any initial operative loss –If we estimate using Difference between baseline & 3 years, orDifference between baseline & 3 years, or All visits (regression)All visits (regression) –Cohort that is used for estimation Whether we use all eyes, 2+FU, eyes w/all visits, etc.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.Want reasonable assurance that endothelial cell density is preserved. –Normal ageing about 0.6% per year Consensus (?) points for concern: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.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%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% CIcalculate sample size using 2.0% upper 90% CI

11. 11 “Steady state” long term loss Percent change from baseline (NOT equivalent to steady state)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 limitAnnual 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 limitAnnual 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 yearRegression-based analyses using all time points produce a loss of 1.7% -2.0% per year Sponsor: 183 eyes w/ baseline count, including baseline, GEESponsor: 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 baselineAlternate: 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 yearsAdditional 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 monthsFor eyes with baseline measurements, virtually no change between baseline and 6 months Piecewise linear model: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 lossData 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 ratePercent 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 timesRegression-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 regressionEstimate 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.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.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: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.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 confidenceDifficult to answer this with any confidence Extrapolation of percentilesExtrapolation of percentiles

18. 18 Estimated outcomes for individual patients Random effect regression, 6 months & subsequent on 2+FU patients. on 2+FU patients.

19. 19 Summary of estimates from individual patient modeling Percentiles 5 %ile 10 %ile 25 %ile 50 %ile Annual rate after 6 months -2.3%-2.2%-2.1%-1.9% Percent change in cells/mm^2 from preop. mean = 2767 cells/mm^2

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?

22. 22