1 Telba Irony, Ph.D. Mathematical Statistician Division of Biostatistics Statistical Analysis of InFUSE  Bone Graft/LT-Cage Lumbar Tapered Fusion Device

2 Statistical Issues Discussed A. Statistical Analyses of Safety and Effectiveness: Bayesian Methods B.Statistical comparison of the use of X-Rays and CT Scans in assessing Spinal Fusions in the InFUSE study

3 A. Statistical Analyses of Safety and Effectiveness: Bayesian Methods Open Surgery Study multi-center (16 sites), prospective, randomized controlled design sample size: 143 investigational and 136 control Two studies were analyzed Laparoscopic Study multi-center (14 sites), prospective, non-randomized controlled (same control as the Open arm) design. sample size: 134 investigational and 136 control

4 Bayesian Statistical Methods were Used Non-Informative Prior distributions Posterior Probabilities as opposed to p-values Predictions of results for 24 months were made for the following cases in which only 12-month data were available:  Patients for which the 24-month values of some endpoints were missing  Patients lost to follow-up  Patients yet not due at 24-months Predictions improved the accountability at 24-months Already high follow-up rates at 24 months were enhanced by the Bayesian model that allowed predictions to be made The predictions improved the precision of the estimates at 24 months

5 Bayesian Posterior Probabilities large probability that ( p 0 - p 1 ) is small enough => evidence that treatment was not inferior than control => equivalence was declared small enough: depends on the endpoint - delta - minimal clinically significant difference large probability: 95%

6 24-Month Results: Open Surgery Group compared to Control Point Estimates and Posterior Probabilities of Equivalence Effectiveness Endpoints

7 24-Month Results: Laparoscopic Group compared to Control Point Estimates and Posterior Probabilities of Equivalence Effectiveness Endpoints The laparoscopic study started later. The percentage of 24-month predictions was higher (~25%).

8 B.Statistical comparison of the use of X-Ray and CT Scans in assessing Spinal Fusions in the InFUSE study 1. Validation Study 2. Scenario in the current submission Problem: False Positive rates. High False Positive rates will inflate the results on Overall Success

9 The Accuracy of X-Ray and CT Assessment of Spinal Fusions Surgical exploration of 53 spinal fusion masses in humans in order to assess the sensitivity and specificity of using X-Rays and CT Scans for determining fusion. Before the surgical exploration (Gold Standard), the fusion status of the patient was determined independently by X- Rays and by CT Scans. Validation study Relevant Parameters Evaluated Sensitivity => Pr (test positive | fused) Specificity => Pr(test negative | non fused) False positive rate => Pr (test positive | non fused)

10 Validation study results (point estimates) * Combined method: In this case the determination was fusion only if both X-Ray and CT Scan determined fusion Conclusion Sensitivity and specificity => higher (better) for CT Scans than for X-Rays. False positive rate => lower for CT Scans than for X- Rays. Smallest false positive rate => Combined X-Ray / CT Scan method (very conservative).

11 The validation study characteristics were different than the ones in the current PMA Patients did not have spinal fusion cages Inclusion Criterion:  Patients with continued or worsening pain following instrumented lumbar fusion for instability or DDD requiring surgery.  As a consequence a higher prevalence of non fusions was expected. However 24 patients were fused and 29 non-fused (even distribution). Time period of exams: approximately 12 months post-op. X-Rays examined were flexion / extension No presence of BMP in the study The method of performing CT Scans was different than the one in the PMA

12 Scenario in the Current Submission The determination of Fusion was based on: evidence of bridging bone:  The determination was first made by X-Ray.  If bridging bone was not detected, CT Scan was used.  If bridging bone was detected by at least one method the evidence of bridging bone was considered present. segmental stability (based on X-Rays) lucent line criteria (based on X-Rays) In addition, second surgery due to pseudoarthrosis was always counted as a failure (regardless of the radiographic fusion determination)

13 Consequently, the actual comparison being made is the difference between the two methods in detecting bridging bone. The other factors (stability, lucent lines, and second surgeries) equally influence both methods. The adopted way of detecting bridging bone is not conservative because it is sufficient to have evidence of bridging bone with one of the methods. There was no case in which presence of bridging bone was detected by X-Ray and not detected by CT Scan. Scenario in the Current Submission

14 Current Submission: Disagreement between X-Rays and CT Scans on determination of fusion based on bridging bone Important In all disagreement cases, CT Scans indicated fusion and X- Rays did not agree. There is less disagreement at 24 months than at 12 months. The relevant endpoint for this PMA is fusion at 24 months.

15 Current Submission: Comparison of Success Rates on Fusion based on Bridging Bone Revealed by X-Rays and CT Scans Note that in some cases for CT Scans, there was a decrease in success rates from 12 months to 24 months. => Are those False Positives at 12 months?

16 Current Submission: Comparison of Overall Success rates when Fusion was based on Bridging Bone Revealed by X-Rays and CT Scans At 12 months the difference is very large. The difference decreases considerably at 24 months.

17 Conclusion The determination of bridging bone has impact on the determination of Overall Success  The impact is much more pronounced at 12 months than at 24 months. A validation study was performed in patients at approximately 12 months after surgery  In that study, both the sensitivity and specificity for CT Scans were higher than for X-Rays.  The characteristics of that study were different than the ones in this PMA.