**MEMORANDUM**

Date: May 19, 2003

From: R. Murty Ponnapalli, Mathematical Statistician, OSB/DBS

> Revised (09/02/03) by Barbara Krasnicka, Mathematical Statistician,
> OSB/DBS

Device: Spectranetics CVX-300 Excimer Laser System

Subject: Statistical Review of P910001/S22, a laser treatment for
Critical Limb Ischemia submitted by Spectranetics Corporation

Through: Dr. Gregory Campbell

Director, Division of Biostatistics

In this submission, the sponsor seeks approval for the use of its
Excimer Laser System in peripheral arteries. A nonrandomized trial using
prospective and retrospective (historical control) studies was used to
demonstrate the evidence of safety and effectiveness of excimer laser
ablation of target vascular obstructions. The laser angioplasty in
critical limb ischemia (LACI) group enrolled 155 limbs of 145 patients
from14 sites (US and German). All patients were poor surgical candidates
with critical limb ischemia (CLI). The treatment in the LACI group was
laser atherectomy plus balloon angioplasty (PTA) and optional stenting
in superficial femoral artery (SFA).

It was agreed at the IDE stage that the study control would be the
control arm of an Italian study published in the Annals of Internal
Medicine, Vol.130, pp 412-421, 1999, by the ICAI study group; the
publication title is "Prostanoids for Chronic Critical Leg Ischemia."

The treatment for patients in the control arm was standard medications
for blockage of arteries and/or surgical interventions at the time of
randomization. Number of patients in the control group was originally
789; however, 116 patients were withdrawn because of some irregularities
in reporting at 5 centers. Therefore, only 673 patients were left in the
control group. The following is the description given by the ICAI group
about the irregularities: "A cross-check of follow-up data through
census offices or the patients themselves or their relatives revealed
incorrect reporting of outcome events for 18 patients followed by five
centers. In the absence of source documents against which to check
individual clinical record forms and in agreement with the International
External Safety and Efficacy Monitoring Committee, all 226 patients
recruited by those centers were excluded from the efficacy evaluation at
6 months."

The following baseline differences in characteristics of legs (observed
in the treatment and control arms) were found to be statistically
insignificant: Rutherford categories 4 and 5 or 6, ulcers or gangrene,
and previous interventions. The baseline characteristics found to be
statistically significantly different were rest pain, previous minor and
major amputation.

According to the clinical protocol of the study under review, the
primary effectiveness endpoint is the percentage of alive patients
without amputations at 6 months and the primary safety endpoint is the
percentage of deaths during the 6-month follow-up period. The summary of
events in the treatment and control arms are given in the following
table.

  ------------------- ------------ ------------ ------------- -------------
  Table 1.                                                    

                      LACI Group   LACI Group   Control Group Control Group

                      Patients     Limbs        Patients      Mortality
                                                              Data

                                                              Patients

  Patient Status                                               

                                                              

  At the baseline     145          155          789           789

  Withdrawn                                     116           

  In the analysis     145          155          673           789

  Lost to follow-up   11(7.6%)     11(7.1%)     7( 1%)        5

                                                              

  Completed the study 134          144          666           

                                                              

  Death               15           17           96            113

  Major Amputation    9\*          9\*          76            

                                                              

  Limb Salvage        110          118          494           
  ------------------- ------------ ------------ ------------- -------------

> \* Two additional major amputations occurred in patients who
> subsequently died within the 6-month follow-up (for a total of 11
> major amputations).

The percentage of patients in the present study who were alive without
major amputation at 6 months was 110/145 = 75.9% and the percentage in
the control was 494/673 = 73.4%. The approximate 95% confidence interval
for the difference (treatment-control) turns out to be (-5.3%, 10.2%).
Since this interval includes 0, the two percentages are not
statistically significantly different at 5% level of significance.

The percentage of deaths with the Excimer Laser System was 15/134 =
11.2% and the percentage of deaths in the control was 96/666 = 14.4% (or
113/784 =14.4%, mortality data was available for 784 patients). The
exact 95% confidence interval for the difference in the true percentages
in the treatment and the control is (-11.6%, 4.4%). Again we see that
there is no statistically significant difference in the percentages of
deaths.

The sponsor defines a serious adverse event (SAE) as death, myocardial
infarction, stroke, reintervention of treatment site during concurrent
hospitalization, major perforation necessitating surgical repair, acute
limb ischemia necessitating intravascular intervention or thrombolytic
drugs, amputation due to distal thrombosis, hematoma or false aneurysm
necessitating surgical intervention, nerve injury, or major amputation.
According to this definition, there were SAEs (35.8%) in 48 patients in
the treatment group and in 239 (35.9%) patients in the control group.
These rates were not statistically different. When calculated on a limb
basis, however, the SAEs in the treatment group were 58/144 (40.3%). One
of the SAEs, reintervention, was more frequently observed in the LACI
group (24/134 or 18%) than in the control group (34/666 or 5%)
(p\<0.001). Approximate 95% confidence interval for the difference in
the probabilities of occurrence of reintervention SAE in the LACI and
control groups is (0.061, 0.1951). Since this interval does not include
zero, the estimated difference 0.1281 between two probabilities is
significant at the level 5%.

A survival type analysis was performed in order to evaluate the
differences between the LACI and control groups with respect to times of
occurrence of major amputation and death during 6 months. To compare
freedom from major amputation times for LACI and control groups, the
Wilcoxon and Log-rank tests were applied. The values of the chi-squared
statistics were 1.14 and 1.43, respectively, and the corresponding
P-values were 0.28 and 0.23. There is no difference between the freedom
from major amputation times for the two groups. Again, for evaluations
of the difference of survival times between the two groups, the Wilcoxon
test was used. The value of the chi-squared statistics was 1.86 and the
corresponding P-value was 0.1728. The difference between the two groups
is not significant at the 5% level.

The following predictors for major amputation/death were investigated
using the univariate Cox proportional hazard model: Rutherford category
6, age, previous minor amputation, diabetes, Rutherford category 5-6,
gender, procedure success, straight line flow established, and stented
leg. The significant univariate predictor for major amputation turned
out to be Rutherford category 6. Age was only a predictor of death
within 6 months after randomization. These two variables, age and
Rutherford Category 6, occurred with similar frequencies in LACI and
control group.

Comments

1.  The control (historical) data and LACI group data may not be
    pool-able. These two studies were carried out in different
    countries, and hospitals that are different with respect to patient
    care and other country/hospital characteristics.

2.  The LACI and control patients are not comparable. For example, the
    following baseline characteristics were found to be statistically
    significantly different: rest pain, previous minor amputation, and
    previous major amputation. Additionally, the control group is a
    historical one, based on the published paper. This means that
    detailed information, including raw data at the patient level, are
    not available. The statistical analysis of this kind of the study
    has serious limitations. For example, it is impossible to use the
    propensity scores to remove possible bias due to Rutherford category
    5-6, history of CAD, and gender in comparison of the death rates at
    6 months.

3.  Point estimates, test and confidence intervals for the differences
    between the treatment and the control may not be accurate due to the
    following reasons:

    a.  the study is not a randomized one (historical control)

    b.  there is considerable missing information ( e.g., 8% was lost in
        the follow-up for LACI group)

    c.  multiple imbalanced covariates (e.g., history of major
        amputation at the baseline) could not be considered in the
        covariate adjusted treatment comparisons, because of the
        character of the study (see comment 2)

    d.  in the LACI group, some patients (7% of 145 patients) received
        treatment for two legs, meaning that the primary events are not
        statistically independent (the same patient)

    e.  there is no information on how many legs were 'treated' in the
        control group.

4.  All analyses should be interpreted with caution. The sponsor's
    suggestion that statistical results support the statement that the
    primary efficacy and safety endpoints of the LACI and the control
    group are to be statistically at least equivalent ("LACI provides
    benefit and reduced risk in all outcomes" on page 69 of the Clinical
    Summary) may be not correct.

5.  In the LACI group, treatment was the laser atherectomy plus balloon
    angioplasty and optional stenting in SFA. In the control group, the
    treatment was standard medications for blockage of arteries
    (although sometimes the treatment included the bypass surgery and/or
    others procedures). It is very difficult to evaluate in this study
    the effectiveness of laser device because of the concomitant
    procedures which were not included in the control group treatment.
    For that reason, the statistical consideration given by sponsor does
    not evaluate the excimer laser therapy.

6.  According to the Transatlantic Inter-Society Consensus (TASC)
    published in the Journal of Vascular Surgery, Vol. 31, 1, Part 2,
    Jan. 2000, the primary endpoint for peripheral artery disease should
    consist of nonfatal events that include major amputation, nonhealing
    of ischemic ulcers, ischemic pain, myocardial infarction, and
    ischemic stroke. In the present study, only major amputation is
    taken as the primary efficacy variable and the other components
    recommended by TASC are taken as the secondary endpoints.

> R. Murty Ponnapalli, Ph.D.
>
> Mathematical Statistician
>
> Revised (09/02/03) by Barbara Krasnicka, Ph.D.