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Statistical ReviewDRAFT

Barbara Krasnicka, Ph.D.

FDA, CDRH

Division of Biostatistics

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Objective of the Submission

To present the effectiveness and safety of the Cardica® PAS-Port Proximal Anastomosis System use in patients requiring CABG

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Studies of Interest Submission was based on (utilized results

of) 4 studies The Pivotal Study Conducted under the

Investigational Plan CP2001-01; Study 1 A prospective, nonrandomized, multi-center

follow-up study (CP 2004-03) carried out to evaluate long-term health status of patients from study CP2001-01

The C-Port Study Conducted under the Investigational Plan CP2002-02; Study 2

A prospective, nonrandomized, multi-center follow-up study to evaluate long-term (about 1 year) health status of C-Port patients

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Pivotal Study –General Characteristics

Conducted under the Investigational Plan CP2001-01 Prospective, non-randomized, one-arm Conducted in 2 German and 1 Swiss clinical sites

from June 2002 to March 2003 Objective: Assess ease of PAS-Port device use,

identify any procedural failure, and evaluate safety and efficacy of the PAS-Port System

Undefined hypothesesCarried out without IDE

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Pivotal Study – Plan of Evaluations

Four main evaluations:pre-operative (coronary angiography)

at discharge from hospital (coronary angiography)

three month post-operative assessment

six month post-operative (coronary angiography)

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Primary Effectiveness Endpoint (post-hoc process)

Primary endpoint: Patency of a PAS-Port graft at 6 months assessed by angiographyPatency: stenosis < 50% in the proximal

anastomosis related to a PAS-Port graft The PAS-Port graft patency rate at 6 months is

to be compared to the fixed OPC (OPC: Objective Performance Criterion) number equal 80%

The historical control rate was 85% with lower confidence limit (LCL) of 95% CI equal 80%.

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Other Effectiveness and Safety Endpoints (post-hoc process)

Patency of a proximal anastomosis of a PAS-Port graft at 12 months as assessed by stress ECG

Occurrence and Frequency of MACE (myocardial infarction, mortality and revascularization) at one year estimated in connection with stress ECG

Any adverse event –safety endpoint

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Patient Disposition – CP2001-01

Sixty patients signed consent form Five patients were eliminated based on the intra-

operative screening process. 55 patients finally enrolled in the study (ITT

population) Implantations of the PAS-Port for 47 (85%) patients

were successful Devices were not implanted successfully for 8 (15%)

patients (10 attempts , 10 technical device failures) 6 month evaluation was performed for only 80%

(44/55) of enrolled patients

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Primary Effectiveness Endpoint Main Results

Observed patency rate (based on the angiography at 6 months) is 0.86 (36/42), 95% CI (0.71,0.95)

With patency imputed based on MRI, the patency rate is 0.87 (41/47), 95% CI (0.74, 0.95)

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Primary Effectiveness EndpointSensitivity Analysis

For the ITT population, when considering all technical failures, all grafts in deceased patients and grafts without additional clinical information indicating patency as occluded, the patency rate is 0.72 (43/60), with 95% CI (0.59, 0.83)

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Primary Effectiveness EndpointSummary

Point estimates

Lower confidence limits of the 95% CI for the patency rates for different methods of assessment are all below the recommended 80% level

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MACE Frequencies

Kaplan Meier estimate of MACE frequency rates

MACE is defined as: myocardial infarction, mortality, and revascularization related to the PAS-Port device

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Problems with MACE Evaluations

MACE rate at 6 month +15 days is 13% i.e., much higher than 4.4%

Only 39 (71%) of 55 patients were evaluated at 6 months by angiography

Lack of question on adverse event occurrence history in the so-called ’12 month’ Case Report Form.

7 patients who withdrew at the baseline were re-enrolled for the 2 year evaluation. But only 4 of them received the stress ECG test. Despite that, the sponsor qualified all 7 patients as MACE free during 2 years after procedure

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Safety Endpoint - Results

Summary of Adverse Events

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Safety Endpoint - Problems

Two patients died during the follow-up period between the 6th and 24th month visits

10 technical failures (8 patients) of the device use were not included in the adverse events analysis

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Limitations of Analyses

The effectiveness endpoint was not met either for ITT, or for the per protocol or for the observed populations.

Point estimates, endpoints of confidence intervals may be biased

Post-hoc analyses

Small data set, only 55 patients (60 grafts)

Missing information (only 42 (70%) grafts were evaluated by angiography)

Study was carried out without IDE

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Limitations of Analyses

Procedures performed in only 3 sites outside US

Comparison of 12 month MACE rates for the pivotal study with the CABG historical data is inadequate.

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CP2002-02 Study – General Characteristics

Prospective, non-randomized, multi-center (4 in Germany and 1 in Switzerland) study

Objective was to assess safety and effectiveness of the C-Port Distal Anastomosis System

Some patients (52/118 = 44%) with multiple vein grafts received the PAS-Port device

The PAS-Port placement was based on surgeons’ discretion and was determined by aorta disease state and preferred grafting sequence.

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Cohort 2 - Characteristics A subset of the CP2002-2 data used as a

complementary data set for the pivotal study Not a separate clinical study Data set on the PAS-Port system for Cohort 2

was created without stringent clinical rules normally imposed on device clinical studies

Data extracted from a broader data set collected for other purposes

Biases embedded in the data impossible to estimate .

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Comparisons of Studies Evaluation of the PAS-Port system in Cohort 2 was

retrospective in conjunction with evaluation of another not approved by the FDA anastomosis system

The PAS-Port systems used in pivotal study and Study 2 were not exactly the same; the PAS-Port System was improved during and after pivotal study

Populations of two studies were different with respect to patients’ pre-operative variables (e.g., angina, age, CCS class) and intra-operative covariates (e.g., duration of surgery)

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Comparisons of Studies-Propensity Score

The sponsor presented justification of pool-ability of the two data sets using the propensity score method

Propensity score may be used to some extent as a diagnostic tool to show comparability between the pivotal study cohort and Cohort 2

If two groups overlap well enough in terms of propensity scores, then it is possible to check the influence of ‘cohort effect’ on the outcome variable adjusted for baseline differences.

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Propensity Score

The propensity score for a patient can be defined as a conditional probability of patient being assigned to Cohort 2, given the patient’s covariates

Can be used to balance the covariate differences of two groups

Can be seriously degraded if important covariates have not been collected or not taken into account in the analysis

Most of the observed covariates should be considered in the analysis.

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Sponsor’s Propensity Score Analysis

The propensity score analysis was carried out in two steps: 1. predictors of angiographic patency (diabetes,

smoking history, vessel disease) were found2. the propensity scores were calculated for each

patient based on patency predictors Based on the propensity scores, the sponsor

grouped patients into three sub-groups and compared the outcome variable adjusted for baseline differences (p=0.22)

The sponsor claimed that the pool-ability of two data sets was justified.

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Distribution of Sponsor’s Propensity Score

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Limitation of the Sponsor’s Analysis

Sponsor’s propensity score analysis could not provide statistical justification that results from two cohorts were poolable because:Propensity scores were based only on three

covariates which were predictors of patencySome important covariates (e.g., duration of

operation..) were not included in the analysisData set was very small

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Propensity Score Analysis Model Building

A logistic regression model with a stepwise selection was utilized to build the propensity score model

The final propensity score model included the following covariates: Age, Angina, CCS, Gender, Hyperlipidemia, Vessel disease, NYHA, # of proximal anastomosis, Use of aspirin within 5 days of operation

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Model Building

The entire population (109 pts) was divided into propensity score third-tiles, with 36 patients in each third-tile

One patient was excluded because she/he did not have CCS

Most patients from Cohort 2 was in the in 3rd and 2nd third-tiles (36 and 16 patients, respectively)

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Propensity Score Distribution

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Conclusion of Propensity Score Analysis

Propensity score distributions for the pivotal study and Cohort 2 do not overlap at all and do not support the sponsor’s pool-ability conclusion

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Final Conclusions

No statistical support for combining two data sets (Pivotal Study and Cohort 2) does exist. Therefore, no statistical analysis for the combined data will be presented

A subset of the CP2002-2 data ( Cohort 2) is not a separate clinical study

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Final Conclusions

Pivotal Study alone did not supply evidence of effectivness and safety of the PAS-Port System

Point estimates for the effectiveness and safety endpoints may be biased due to:

Post-hoc analyses

A lot of missing information (in some cases, the imputed patency is questionable).

Small data set