# Presentation: 666109

## 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

- 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

## Eye accountability

| No baseline, 1 subsequent visit | 24 |
| --- | --- |
| No baseline, 2+ subsequent | 70 |
| Baseline, 1 subsequent | 6 |
| Baseline, 2 subsequent | 34 |
|      last visit at 1 year |      13    |
|                        2 years | 10 |
|                        3 years |      11 |
| Baseline, 3+ subsequent | 172 |
|      last visit at 2 years |      24 |
|                        3 years |      91 |
|                        4 years | 57 |
| TOTAL | 306 |

## Other combinations of visits

| 3 and 4 year visits | 57 |
| --- | --- |
| Baseline and 4 year visits | 57 |
| Baseline, 3 and 4 year visits | 51 |
| All visits up to 3 years | 67 |
| All visits up to 4 years | 37 |

## ECD results for all eyes and visits

## Mean cell counts for various cohorts

| COHORT | n | BL | 3 mo | 1 yr | 2 yr | 3 yr | 4 yr |
| --- | --- | --- | --- | --- | --- | --- | --- |
| All patients | 306 | 2657 | 2571 | 2544 | 2476 | 2434 | 2355 |
| BL,2+ | 206 | 2654 | 2594 | 2565 | 2498 | 2406 | 2370 |
| 3,4 yr. | 57 | 2608 | 2505 | 2478 | 2428 | 2355 | 2356 |
| All visits | 37 | 2614 | 2515 | 2486 | 2408 | 2317 | 2345 |

## 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

## “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.

## 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.

## Two different fits

## Extrapolation from different fits

## 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.

## 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

## 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?

## Regression on individual eyes

- Piecewise linear fits to 206 individual eyes (BL, 2+ cohort).

## 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%)

## 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.

## Clinically significant ACD effect?

- Annual cell loss estimated using per-eye regressions.

## Sponsor’s ACD summary

| Parameter |  | Estimate | P-Value |
| --- | --- | --- | --- |
| Intercept |  | -0.9495 | 0.1017 |
| Visit interval | 1 Year to 2 Years | -0.2328 | 0.7125 |
|  | 2 Years to 3 Years | -0.9465 | 0.1886 |
|  | 3 Months to 1 Year | 1.2483 | 0.0650 |
|  | Pre-op to 3 Months | 0 |  |
| ACD group | 2.80 to 3.00 mm | -2.6544 | 0.0015 |
|  | >3.00 to 3.50 mm | -0.9729 | 0.0263 |
|  | >3.50 to 4.00 mm | -1.4923 | 0.0026 |
|  | >4.00 mm | 0 |  |

- Estimates are percent loss relative to index group.

## Questions for panel

## Slide 21