# Presentation: 550538

## Statistical Issues for PMA P050034Implantable Miniature Telescope (IMT)

- T.C. Lu and Yao Huang
- Cardiovascular and Ophthalmic Branch
- Division of Biostatistics
- Office of Surveillance and Biometrics
- Center for Devices and Radiological Health
- July 14, 2006

## Major Issue

- To investigate the effects of device on Endothelial Cell Density (ECD) over time.
- Analyses are based on 24-month follow-up data.
- Both IMT and fellow eye data are used.

## ECD scatter-plots

## Issues to be Discussed

- Mean ECD loss over time
- Acute vs. chronic loss
- Distribution of ECD loss over time
- proportion of patients with ECD loss > 10%, 50% for IMT eyes and fellow eyes
- Other clinical variables may affect ECD: ACD and surgical order (surgeon experience)
- Modeling of ECD data – how long would it take for an IMT-implanted eye to reach ECD 1000 or lower?

## Mean ECD Percent Loss  (IMT eyes)

- Acute ECD loss associated with surgery (baseline-3 months):
- Mean: 20%;  95% CI (17%, 23%)
- Chronic ECD loss associated with continuous use of device (3-24 months):
- Mean: 9.7%;  95% CI: (6.3%, 13.0%) or
- Mean annual loss = 5.4%;  95% CI  (2.0%, 8.8%)

## Mean ECD Over Time

## Mean ECD Over Time

## 2. % of Eyes with ECD Loss >10% 

## % of Eyes with ECD Loss >50%

## ECD % Change for IMT eyes

| Time
(month) | Percentiles |  |  |  |
| --- | --- | --- | --- | --- |
|  | < 5 % | < 10 % | < 20 % | < 50 % |
| 0-3 | -67% | -52% | -37% | -14% |
| 3-24 | -35% | -27% | -19% | -8% |
| 0-24 | -75% | -59% | -43% | -24% |

## 3. Other Clinical Factors that May Affect ECD 

**Anterior Chamber Depth (ACD)**
**Mean = 3.147mm (IMT eyes)**
**S.D. = 0.380mm**
**Range = (2.48mm, 4.74mm)**
**Surgical order (**_**<**_**3****rd**** case, **_**>**_**4****th**** case) **

## Sponsor’s Results 

**ACD has a linear effect (p<0.05) on ECD % change from baseline to 3 months, but not from 3 months to 24 months.**
**Surgical orders (surgeon experiences) did not show statistically significant difference.  **

## 4. The Modeling Results of the ECD data

## ECD data by patients

## A Mixed Effect Model

## Model Fitting Results

| Effect | Estimate | Standard Error | 
2-sided 
p-value |
| --- | --- | --- | --- |
| Intercept | 2466.89 | 19.75 | < 0.0001 |
| Acute monthly change for IMT Eye | -169.81 | 14.28 | < 0.0001 |
| Chronic monthly change for IMT Eye | -9.83 | 1.38 | < 0.0001 |
| Acute monthly change for Fellow Eye | -6.59 | 4.61 | 0.1532 |
| Chronic monthly change for Fellow Eye | -3.03 | 1.05 | 0.0039 |

## Comparison of Slopes

| Comparison | 2-sided p-value |
| --- | --- |
| Acute ECD slopes between IMT & Fellow eyes (-169.81 vs. -6.59) | < 0.0001 |
| Chronic ECD slopes between IMT & Fellow eyes (-9.83 vs. -3.03) | < 0.0001 |
| IMT eyes: acute slope vs. chronic slope (-169.81 vs. -9.83) | < 0.0001 |
| Fellow eyes: acute slope vs. chronic slope (-6.59 vs. -3.03) | 0.4863 |

## Caveats of Data Extrapolation

**Always**** a questionable exercise to extrapolate beyond the range of available data.**
**Highly dependent on the model & assumptions.**
**Linear? Exponential? Other?**
**Also should consider:**
**If it is necessary to obtain good long-term data.**
**If so, how to go about it.**

## Data Extrapolation to Year 4

## Percentage of Eyes with Predicted ECD≤1000

|  | IMT eyes | Fellow eyes |
| --- | --- | --- |
| 2 years | 24/216 (11.1%) | 1/216 (0.5%) |
| 3 years | 38/216 (17.6%) | 2/216 (0.9%) |
| 4 years | 49/216 (22.7%) | 3/216 (1.4%) |

## Baseline ECD Quartiles of IMT Eyes

|  | ECD |
| --- | --- |
| < Q1  | 1695.00 ~ 2261.33 |
| Q1 ~ median  | 2261.33 ~ 2513.00 |
| Median ~ Q3  | 2513.00 ~ 2772.17 |
|  > Q3  | 2772.17 ~ 3356.00 |

## Prediction of Eyes with ECD≤1000 at Year 2

|  | IMT Eyes | Fellow Eyes |
| --- | --- | --- |
| Baseline ECD < Q1  | 11/54 (20.4%) | 1/54 (1.9%) |
| Baseline ECD in Q1 ~ median  | 4/54 (7.4%) | 0 |
| Baseline ECD in Median ~ Q3  | 5/54 (9.3%) | 0 |
| Baseline ECD > Q3  | 4/54 (7.4%) | 0 |

## Projection of Eyes with ECD≤1000 at Year 3

|  | IMT Eyes | Fellow Eyes |
| --- | --- | --- |
| Baseline ECD < Q1  | 17/54 (31.5%) | 2/54 (3.7%) |
| Baseline ECD in Q1 ~ median  | 8/54 (14.8%) | 0 |
| Baseline ECD in Median ~ Q3  | 9/54 (16.7%) | 0 |
| Baseline ECD > Q3  | 4/54 (7.4%) | 0 |

## Projection of Eyes with ECD≤1000 at Year 4

|  | IMT Eyes | Fellow Eyes |
| --- | --- | --- |
| Baseline ECD < Q1  | 21/54 (38.9%) | 2/54 (3.7%) |
| Baseline ECD in Q1 ~ median  | 12/54 (22.2%) | 0 |
| Baseline ECD in Median ~ Q3  | 11/54 (20.4%) | 1/54 (1.9%) |
| Baseline ECD > Q3  | 5/54 (9.3%) | 0 |

## Baseline Demographics for IMT Eyes

|  | Baseline ECD | Age       (SD) | ACD     (SD) |
| --- | --- | --- | --- |
| Baseline ECD < Q1  | 1695.00 ~ 2261.33 | 76.81   (6.75) | 3.10    (0.38) |
| Baseline ECD in Q1 ~ median  | 2261.33 ~ 2513.00 | 75.97   (6.42) | 3.13    (0.38) |
| Baseline ECD in Median ~ Q3  | 2513.00 ~ 2772.17 | 76.01   (7.15) | 3.18    (0.40) |
| Baseline ECD > Q3  | 2772.17 ~ 3356.00 | 75.44   (8.72) | 3.18    (0.37) |

## The Sponsor’s Modelon ECD Data

- Three piecewise linear function with two breakpoints at : t=3 and t=9 months
- Only data of IMT eyes used
- Results are consistent with those of the Agency’s model for IMT eyes

## Results of Using Two Breakpoints

| Effect | Estimate | Standard Error | 
2-sided 
p-value |
| --- | --- | --- | --- |
| Intercept | 1798.53 | 206.20 | <0.0001 |
| Month (<3M) | -329.37 | 72.08 | <0.0001 |
| Month (3 to 9M) | -17.63 | 3.38 | <0.0001 |
| Month (>9M) | -5.76 | 1.61 | 0.0004 |
| ACD | 180.55 | 64.42 | 0.0053 |
| ACD*Month (<3M) | 64.34 | 22.72 | 0.0048 |

## Predicted Probability of ECD <1000 cells/mm2 at 4 Years by Sponsor

| Baseline ECD | ACD=2.5 | ACD=3.0 | ACD=3.5 | ACD=4.0 |
| --- | --- | --- | --- | --- |
| 2500 | 0.149 | 0.116 | 0.089 | 0.067 |
| 2000 | 0.398 | 0.341 | 0.288 | 0.238 |
| 1600 | 0.644 | 0.587 | 0.527 | 0.467 |

## Conclusions

**For the group of IMT-implanted eyes, ECD decreases throughout the study. **
**Slopes of acute and chronic periods are both significantly different from zero. **
**The chronic ECD loss can not be ignored.**

## Conclusions (cont.)

**At both acute and chronic periods, the slopes are significantly different between the IMT eyes and fellow eyes, which suggests that there is a significant treatment (IMT implantation) effect in ECD change. **

## Question for Panel

**	****Does the data presented provide reasonable assurance of safety in terms of ECD loss for this device?**

## Slide 32