# Presentation: 678784

## Statistical Analysis of

**Telba Irony, Ph.D.**
**Mathematical Statistician**

**Division of Biostatistics**

**Statistical Analysis of**
**InFUSE******** Bone Graft/LT-Cage Lumbar Tapered Fusion Device**

**Notes:**
I’m Telba Irony, the statistical reviewer for the McGhan studies.
In this presentation, I will comment on the statistical techniques that were used in the design and analysis of the studies presented by the sponsor. I will also point out to possible biases that should be taken into account when the results of the study are analyzed.

## 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**

## 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**

## 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**

## large probability that (p0- p1) is  small  enough =>

- 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%

## 24-Month Results: Open Surgery Group compared to Control

**Point Estimates and Posterior Probabilities of Equivalence**
**Effectiveness Endpoints**

## 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%).

## 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**

## 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)**

## 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).**

## 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 **

## 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)**

## 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**

## 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.**

## 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?

## 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.

## 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.**