1. P970043/S10 Alcon LADARvision Excimer Laser System FDA Review and Questions for Ophthalmic Devices Panel August 1, 2002

2. FDA Review Team:  Jan Callaway (team leader)  Malvina Eydelman (primary clinical)  Gene Hilmantel (vision, clinical)  Bruce Drum (vision, clinical, engineering)  Dexiu Shi (vision, engineering)  Woody Ediger (engineering)  Lilly Yue (statistics)

3. Introduction  FDA has no clinical questions for the Panel regarding basic safety or effectiveness.  FDA wishes to ask the Panel’s advice on issues specific to higher-order aberration treatments: –analysis and interpretation of the results; –information needed to support specific effectiveness claims; and –labeling information.

4. Comparison of Custom and Conventional Treatment Outcomes  The outcomes of the 139-eye effectiveness cohort were compared to the outcomes of 47 conventionally treated eyes at 6 months after surgery.

5. Comparison of Custom and Conventional Treatment Outcomes  Higher-order aberrations were smaller after Custom than conventional treatment.  Aberrations were reduced (pre-op to 6 months) in 38% of Custom eyes vs. 14% of conventional eyes.  Custom treatment improved image quality as much as  0.2 D reduction of spherical blur.

6. Comparison of Custom and Conventional Treatment Outcomes  Relative to pre-op, mean post-op contrast sensitivity was 0.1-0.2 log unit higher for Custom eyes than for conventional eyes.  Relative to pre-op, mean contrast sensitivity increased for Custom eyes and decreased for conventional eyes.

7. Questions About Custom/Conventional Comparison 1.What differences (if any) between Custom and conventional outcomes are clinically and/or functionally significant? What labeling claims are supported by these differences. 2.Are additional clinical data, analyses or criteria needed to evaluate the relative effectiveness of Custom and conventional treatments with regard to higher order aberrations and visual function?

8. Analysis of Higher-Order Aberrations  Zernike Polynomial Expansion Analysis –2 nd order (defocus, astigmatism) –3 rd order (coma, trifoil) –4 th order (spherical aberration, secondary astigmatism, tetrafoil)  Root Mean Square (RMS) Variability –Standard deviation of wavefront elevation –Overall vs. term-by-term RMS

9. Analysis of Higher-Order Aberrations  Functional significance of higher order aberrations is not always evident.  Different Zernike terms with same RMS may have different effects.  Elimination of all aberrations may not be optimal; e.g., some spherical aberration may be beneficial.  Zernike parameters depend on pupil size.  Can Higher-Order Aberrations be compared to “equivalent defocus”?

10. Questions About Aberration Analysis 3.What information about measurement, analysis, and correction of higher order aberrations is needed in the labeling to inform physicians and patients about safety and effectiveness of CustomCornea treatments?

11. Current Stability Criteria  Refractive change ≤1.0 D for ≥95% of eyes between 1 and 3 months or over a minimum 3- month period thereafter.  Mean rate of refractive change ≤0.5 diopter/year.  Rate of refractive change is zero or decreasing over time at stability.  95% confidence interval around mean change includes zero.  Time after stability confirms other criteria.

12. Stability of Aberration Corrections  Existing stability criteria are insensitive to changes in higher order aberrations.  Effects of correcting higher order aberrations are smaller than effects of correcting sphere and cylinder, suggesting that sphere and cylinder instabilities could disrupt higher order corrections.

13. Questions About Stability Criteria 4.What additional stability criteria are needed for higher order aberration treatments? 5.Should stability criteria be more stringent for wavefront-based treatments than for conventional treatments?

14. FDA Questions for Panel 1.What differences (if any) between Custom and conventional outcomes are clinically and/or functionally significant? What labeling claims are supported by these differences.

15. FDA Questions for Panel 2.Are additional clinical data, analyses or criteria needed to evaluate the relative effectiveness of Custom and conventional treatments with regard to higher order aberrations and visual function?

16. FDA Questions for Panel 3.What information about measurement, analysis, and correction of higher order aberrations is needed in the labeling to inform physicians and patients about safety and effectiveness of CustomCornea treatments?

17. FDA Questions for Panel 4.What additional stability criteria are needed for higher order aberration treatments?

18. FDA Questions for Panel 5.Should stability criteria be more stringent for wavefront-based treatments than for conventional treatments?