Telba Irony, Ph.D. Mathematical Statistician

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

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 Two studies were analyzed • Open Surgery Study • multi-center (16 sites), prospective, randomized controlled design • sample size: 143 investigational and 136 control • 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 (p0- p1) 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. Validation study 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. 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. Scenario in the Current Submission • 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.

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.