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

group control in theendpoint for the success of chance :p0

group treatmentin theendpoint for the success of chance :p1

• 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%

Treatmentn better tha is Control large is pp If 10

.ppabout Think 10

Treatment than worseis Control (small) negative is pp If 10

6

24-Month Results: Open Surgery Group compared to ControlPoint Estimates and Posterior Probabilities of Equivalence

Effectiveness Endpoints

VariableChanceSuccessTreat.

ChanceSuccessControl

Probab.Equivalence

Fusion 92.8% 88.1% ~100%

OswestryPain

71% 70.9% 99.6%

NeurologStatus

81% 81.7% 96.7%

Back Pain* 72.4% 75.8% 87.8%

Leg Pain 78.2% 72.5% 99.8%

SF-36PCS

83.1% 82.1% 98.9%

SF-36MCS*

66% 69% 87.3%

IVDH 92.6% 94.5% 99.3%

OverallSuccess

57.1% 56.7% 99.4%

7

24-Month Results: Laparoscopic Group compared to ControlPoint Estimates and Posterior Probabilities of Equivalence

Effectiveness Endpoints

The laparoscopic study started later.The percentage of 24-month predictions was higher (~25%).

VariableChanceSuccessTreat.

ChanceSuccessControl

Probab.Equivalence

Fusion 93% 88.1% ~100%

OswestryPain

83% 70.9% ~100%

NeurologStatus

89% 81.7% 99.9%

Back Pain 80.8% 75.9% 99.4%

Leg Pain 78.4% 72.5% 99.6%

SF-36PCS

91.8% 82.1% ~100%

SF-36MCS

71.1% 68.9% 97.6%

IVDH 92.9% 94.4% 98.6%

OverallSuccess

68% 56.6% ~100%

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).

Sensitivity Specificity FalsePositives

X-Ray 79.2% 86.2% 13.8%

CT-Scan 87.5% 93.1% 6.9%DiagnosticTechnique

X-Ray andCT- Scan* 75% 100% 0%

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.

Open group Control group Laparoscopicgroup

proportiondisagreements

% proportiondisagreements

% proportiondisagreements

%

12 months 52/130 40 73/119 61 42/99 4224 months 9/124 7.3 5/112 4.5 0 0

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?

12-Month Success Rates for FusionOpen Control Laparoscopic

X-Rays 57.3% 30.5% 48.6%CT Scans 96.9% 92.4% 93.9%

24-Month Success Rates for FusionOpen Control Laparoscopic

X-Rays 87.4% 83.6% 94.2%CT Scans 94.4% 88.4% 94%

16

Current Submission: Comparison of Overall Success rates when Fusion was based on Bridging Bone Revealed by X-Rays

and CT Scans

12-Month Overall Success RatesOpen Control Laparoscopic

X-Rays 32.1% 19.4% 35.4%CT Scans 59.7% 60.2% 68.6%

At 12 months the difference is very large.The difference decreases considerably at 24 months.

Primary Endpoint24-Month Overall Success Rates

Open Control LaparoscopicX-Rays 54.2% 54.6% 68.1%

CT Scans 58.5% 55.9% 67%

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.