SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

SUMMARY

OF

SAFETY

AND

EFFECTIVENESS

DATA

(SSED)

I.

GENERAL

INFORMATION

Device

Generic

Name:

Drug-Eluting Coronary

Stent System

(NIQ)

Device

Trade

Name:

IONTM

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System

(MonorailM)

IONTM

Paclitaxel-Eluting

Platinum Chromium

Coronary

Stent

System

(Over-The-Wire)

Applicant's

Name

and

Address: Boston

Scientific

Corporation

One

Scimed

Place

Maple Grove,

MN

55311

Date(s)

of Panel Recommendation:

None

Premarket

Approval

Application

(PMA)

Number:

P

100023

Date

of

FDA

Notice

of

Approval:

April 22,

2011

Expedited:

Not

Applicable

II.

INDICATIONS

FOR

USE

The

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary Stent System (Monorail

and

Over-The-Wire

Systems)

is

indicated

for

improving

luminal

diameter

for

the

treatment

of

de

novo

lesions

in

native coronary

arteries

>

2.25

mm to <

4.00

mm

in

diameter

in

lesions

<

34

mm

in

length.

III.

CONTRAINDICATIONS

Use

of

the

ION

Paclitaxel-Eluting Platinum

Chromium

Coronary

Stent

System

is

contraindicated

in

patients

with:

*

Known

hypersensitivity

to

316L

stainless

steel

or

platinum

*

Known

hypersensitivity

to

paclitaxel

or

siructurally

*

Known hypersensitivity

to the

polymer

or

its

individual

components

(see

details

in

Section

4

-

Product

Description

below)

Coronary

Artery

Stenting

is

contraindicated

for

use

in:

*

Patients who

cannot

receive

recommended

antiplatelet

and/or anticoagulant

therapy

*

Patients

judged

to

have

a

lesion

that

prevents complete

inflation

of

an

angioplasty

balloon

or

proper

placement

of

the

stent

or

delivery

device

PMA P100023:

FDA

Summary

of

Safety and

Effectiveness

Data

Page

1

IV.

WARNINGS

AND

PRECAUTIONS

The

warnings

and

precautions

can be

found

in

the

ION

Paclitaxel-Eluting

Platinum

Chromium Coronary

Stent

System

Directions

for

Use

(DFU).

V.

DEVICE

DESCRIPTION

The

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System

is

a

device/drug

combination

product comprised

of

two

regulated

components:

*

A

device

(Element

Coronary

Stent System)

*

A

drug

(a

formulation

of

paclitaxel

contained

in

a

polymer

coating).

The characteristics

of

the

ION

stent

system

are

described

in

Table

1

below.

Table

1:

ION

Stent

System

Product

Description

ION

Stent

ION

Stent

Monorail

Stent

Delivery

System

Over-The-Wire

Stent

Delivery

System

Available

Stent

8,

12,

16,

20,

24,

28,

32,

38

Lengths

(mm)

Available

Stent

Dilaete

(m2.25*,

2.50*,

2.75,

3.00,

3.50,

4.00

Diameters

(mm)

Stent

Material

Platinum

Chromium

Alloy

(PtCr)

Stent

Strut

0.0032

in

(0.08

1mm)

for

diameters

2.25 mm

to

3.50

mm

Thickness

0.0034

in

(0.086

mm)

for

diameter

4.00

mm

Drug

Product

A

conformal

coating

of

a

polymer

carrier

loaded

with

I

jig/mm

2

paclitaxel

applied

to

the

stent

with

a

maximum nominal

drug content

of

247pg

on

the largest

stent (4.00

x

38mm)

Delivery

System

143

cm

Effective

Length

Single

access

port

to

inflation

lumen.

Y-Connector

(Side

arm

for

access

to

balloon

Delivery

System Guidewire

exit

port

is

located

inflation/deflation

lumen.

Straight

arm

is

Y-Adapter

Ports

approximately

26

cm

from

tip. Designed continuous

with

shaft

inner

lumen).

Designed

for

guidewire

<

0.014

in

(0.36

mm)

for

guidewire

<

0.014

in

(0.36 mm)

A

balloon,

with

two

radiopaque

markers,

nominally

placed

0.385

mm (0.015

in)

beyond

the

stent

at

each

end.

Nominal Inflation

Pressure:

*

Diameters

2.25 mm,

2.50

mm, 2.75 mm,

3.00 mm, 3.50 mm,

4.00

mm;

11

atm

(1115

Balloon

Inflation

kPa)

Pressure

Rated

Burst

Inflation

Pressure:

*

Diameters

2.25

mm;

18

atm

(1824

kPa)

*

Diameters

2.50 mm,

2.75

mm,

3.00 mm,

3.50

mm,

4.00

mm;

16atm

(1621

kPa)

3.4

F

(1.20

mm)

proximal

for

2.25 to

4.00

mm

sizes

Catheter

Shaft

2.3

F

(0.80 mm)

proximal

and 2.4

F

(0.85

mm)

distal for

2.25 to 2.75

mm

Outer

Diameter

2.7

F

(0.95

mm)

distal

sizes

2.7

F

(0.95

mm)

distal

for 3.00

to

4.00

mm

sizes

Guide

Catheter

Minimum

Inner

0.056

in

(1.42)

for

2.25 to 3.50

mm

sizes

>0.066

in

(1.68)

Diameter

0.058

in

(1.47)

for

4.00

mm

sizes

Requirement

*

2.25

and

2.50

mm

sizes

are

available in

8,

12,

16,

20, 24,

28, 32

mm

lengths

PMA

P100023:

FDA

Summary

of

Safety and

Effectiveness

Data

Page

2

A.

Device

Component

Description

The

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System (hereafter

referred

to

as

'ION')

consists

of

a

drug

coated

balloon expandable

stent,

pre-mounted

on

a

high-

pressure

delivery

catheter, similar

to

the

commercially

available

Apex

PTCA

Dilatation

Catheter.

The

stent

is

made

from

a

Platinum

Chromium Alloy

(PtCr).

The

drug

coating

is

composed

of

two

components:

a

polymer

carrier

matrix

material,

poly(styrene-isobutylene-

styrene) referred

to

as

SIBS

(also

known

by

its

commercial name

TransluteTm)

and

an

active

pharmaceutical

ingredient,

paclitaxel.

Each

stent

is

coated

with

1

[ig

paclitaxel per

mm

2

of

stent

surface

area

in

an

8.8%

formulation

(weight

percent

paclitaxel

in

the

polymer

coating). This

is

the

same

dose

density

and

formulation

used

on the

commercially

available

TAXUS®

Express

2

@

Paclitaxel-Eluting

Coronary

Stent System

(P030025) and

TAXUSO

Libert6o

Paclitaxel-

Eluting Coronary

Stent

System (P060008).

PtCr

was

selected

as

the stent

material

as

it

offers

superior strength

and

radiopacity, thus

allowing

the

stent

to

provide

acute

performance

with

thinner

struts

in

a

more

flexible

design.

The

commercial matrix

of

ION

stent

lengths

and

diameters

is

similar

to

the

TAXUS

Express2

and

TAXUS

Libertd

device

matrices. Although

the

matrix

includes

the same

vessel

diameter

range

of

2.25

-

4.00 mm,

ION

has

four

(4)

stent

models

as

compared

to

three

(3)

models

for

TAXUS

Libert6

and

two

(2)

models

for

TAXUS

Express

2.

The

four

(4)

ION

stent

models

are:

*

Small

Vessel

(SV):

2.25

mm

*

Small

Workhorse

(SWH):

2.50

-

2.75

mm

*

Workhorse

(WH):

3.00

-

3.50

mm

*

Large

Vessel

(LV):

4.00mm

The

commercial

matrix

is

shown

in

the

Table

2

below:

Table

2:

ION

Stent

System

Product

Description

A.

D

Stent

Model

Stent

Length

(mm)

u

Tesign

Diameter

(mm)

8

12

16

20

24

28

32

38

C

SV

2.25

x

2.50

x

0

SWH

m

2.75

x

x x

-x

P

WH

3.00

x

x x

o

3.50

x

nLV

4.0

x

x x

x

e

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

3

B.

Drug

Component

Description

The

drug

component

of

the

ION

Paclitaxel-Eluting Platinum

Chromium

Coronary

Stent

System

consists

of

paclitaxel

(the active

ingredient)

and

TransluteTM

polymer

carrier

(the

inactive

ingredient).

B3.

Paclitaxel

The

active

pharmaceutical

ingredient.

in

the

ION

stent

is

paclitaxel.

It

is

a

white

powder,

isolated

from

a

spectrum

of

Taxus

species

and

hybrids.

The

chemical

name

of

paclitaxel

is:

Benzenepropanoic

acid,

P-(benzoylamino)-a-hydroxy-,6,12bbis(acetyloxy)-12-

(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12bdodecahydro-4,11-dihydroxy-4a,8,13,13

tetramethyl-5-oxo-7,11-methano-1Hcyclodeca[3,4]benz[1,2-

b]oxet-9-yl

ester,[2a

R-

[2aa,4P,4aP,6,9a

(aR*,PS*),

11

a,

1

2a,

12aa,

1

2ba]]-.

Paclitaxel

is

a

diterpenoid

with

a

characteristic

taxane

skeleton

of

20

carbon

atoms,

a

molecular

weight

of

853.91

g/mol

and a

molecular formula

of

C

47

H

51

NO

14

.

It

is

highly

lipophilic,

insoluble

in water,

but

freely

soluble

in

methanol,

ethanol,

chloroform,

ethyl

acetate,

and

dimethyl sulfoxide.

The chemical

structure

of

paclitaxel

is

shown

in

Figure

1.

The

nominal

total

loaded

dose

of

paclitaxel per

nominal

stent

length/diameter

is

shown

in

Table

3

0_

0

-

0

OH

l~J~%..No

....

H17C

4H3

Figure

1:

Chemical

Structure

of

Paclitaxel

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

4

Table

3:

Nominal

Total

Loaded

Dose

of

Paclitaxel

per

Nominal

Stent

Length/Diameter

Nominal

Stent

Length

(mm)

Stent

Model

/

Nominal

S

on

a

e

8

12 16

20 24

28

32

38

Stent

Length

(mm)

SV

39

58

74

94

109

129

148

(2.25

mm)

SWH

Total

loaded

(2.50-2.75

40

62

80

97

115

133

155

181*

dose

mm)

Paclitaxel/Stent

WH

(g)

(3.00-3.50

43

61

86

104

123

141

166

197

mm)

1

LV

S(.m

57

82

107

131

156

181

206

247

(4.00

mm)

*

Applies

to

2.75

mm

diameter

only.

B2.

Inactive

Ingredients

The

only inactive

ingredient

in

the

ION

stent

is

SIBS

[poly(styrene-b-isobutylene-b-

styrene)],

a

tri-block

copolymer

(trade

name:

TransluteTM)

that

is

composed

of

styrene

and

isobutylene units

built

on

1,3-di(2-methoxy-2-propyl)-5-tert-butylbenzene.

It

is

a

hydrophobic elastomeric

copolymer

with

a

molecular weight

(Mn-number

average

molecular weight)

of

80,000 to

130,000

g/mol

and

a

polydispersity

index

of

1.0

to 2.0.

The

polymer

is

mixed

with

the

drug paclitaxel

and

then applied

to

the

stents.

There

is

no

primer

or

topcoat

layer.

The

drug/polymer

coating

is

adhered

to the

entire

surface

(i.e.,

luminal

and

abluminal)

of

the

stent.

The

structural

formula

for

the

polymer

is

shown

in

Figure

2

below.

n

ri

rn

=

repeating

units

of

styrene

n =

repeating

units

of

isobulylene

Figure

2:

The

Chemical

Structure

of

Translutem

Polymer

Carrier

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

5

C.

Mechanism

of

Action

The

mechanism

(or

mechanisms)

by

which

an

ION

stent

affects

neointimal

production

as

seen

in

clinical

studies

has

not

been

fully

established.

Paclitaxel

promotes

the

assembly

of

microtubules

from

tubulin

dimers

and

stabilizes

microtubules

by

preventing

depolymerization.

This

stability

results

in

the

inhibition

of

the

normal

dynamic

reorganization

of

the

microtubule

network

that

is

essential

for

vital

interphase

and

mitotic

cellular

functions.

VI.

ALTERNATIVE

PRACTICES

AND

PROCEDURES

There

are

several

other

alternatives

for

the

treatment

of

patients

with coronary

artery

disease,

which

may

include

exercise, diet, smoking

cessation,

drug

therapy, percutaneous

coronary

interventions

(such

as

angioplasty

and

placement

of

bare metal

stents,

coated

stents,

and

other

drug-eluting

stents), and

coronary

artery

bypass

graft surgery

(CABG).

Each

alternative

has

its

own

advantages

and

disadvantages.

A

patient

should

fully

discuss

these

alternatives

with

his/her physician

to

select the

method that

best

meets

expectations

and

lifestyle.

VII.

MARKETING

HISTORY

The

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent System

is

commercially

available

in

the

following countries:

*

Australia

*

Liechtenstein

*

Austria

*

Lithuania

*

Belgium

*

Luxembourg

*

Bulgaria

*

Malaysia

*

Chile

*

Malta

*

Cyprus

0

Netherlands

*

Czech

Republic

*

Norway

*

Denmark

*

Poland

*

Estonia

*

Portugal

*

Finland

*

Romania

*

France

*

Russia

*

Germany

*

Saudi

Arabia

*

Great

Britain

*

Singapore

*

Greece

*

Slovakia

*

Hungary

a

Slovenia

*

Iceland

*

South

Africa

*

India

a

Spain

*

Ireland

*

Sweden

*

Italy

*

Switzerland

*

Latvia

*

Tunisia

*

Lebanon

*

United

Arab

Emirates

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

6

As

of

March

31,

2011,

approximately

29,257

ION

Stents

have

been

distributed

outside

the

U.S.

No

products

have

been

withdrawn

from

the

market

in

any

country

for

any

reason.

VIII.

SUMMARY

OF

PRECLINICAL

STUDIES

A

series

of

non-clinical

laboratory

studies

were

performed

to

evaluate:

*

the

stent

and

the

stent

delivery

system

[i.e.,

the

stent

on

either

the

Monorail

(MR)

or

Over-The-Wire

(OTW) stent

delivery

system

(SDS)]

*

the

polymer

substance

[i.e.,

poly(styrene-isobutylene-styrene)

(SIBS)]

*

the

drug

substance

(i.e.,

paclitaxel)

*

the

finished

combination

product

(i.e.,

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary Stent)

A.

Biocompatibility Studies

A

series

of

Good

Laboratory

Practice

(GLP)

biocompatibility

tests

were

conducted

to

demonstrate

that

the

components

of

the

IONTM

Paclitaxel-Eluting

Platinum Chromium

Coronary

Stent

System (Monorail

and

Over-The-Wire)

are

biocompatible.

Testing

was

conducted

separately

for

the

stent

implant

and

the

stent

delivery

system.

Tests

were

conducted

on

ethylene

oxide-sterilized

bare

metal

(Platinum Chromium

Alloy

(PtCr))

stents,

and

stent delivery systems. These

test

articles

were

processed

in

a

manner

similar

to

the

finished

IONTM

product.

There were

some

minor

manufacturing

differences

which

were

determined not

to

impact

the

biocompatibility

of

the final

device.

Biocompatibility

data

on

the drug

substance, Paclitaxel,

and

SIBs

coating was

incorporated

by

reference

to

P060008

for the

Taxus

Liberte

Paclitaxel-Eluting

Coronary

Stent

System

and

is

applicable

to

the

IONTM

Paclitaxel-Eluting Platinum

Chromium

Coronary

Stent System

because

the

coating process,

amount

of

coating

per

unit

area,

drug

substance

total dose

and

dose

per

unit

area,

and

sterilization

processes

are

equivalent

for the

Liberte

and

ION

stents.

All

biocompatibility testing

was

conducted

in

accordance

with:

*

Guidance

for Industry

and

FDA

Staff:

Non-Clinical

Tests

and

Recommended

Labeling

for

Intravascular

Stents

and

Associated

Delivery Systems,

January

13,

2005

*

Draft Guidance for

Industry:

Coronary Drug-Eluting

Stents

-

Nonclinical

and

Clinical Studies

Companion Document,

March

2008

*

Draft Guidance

for

Industry:

Coronary Drug-Eluting

Stents

-

Nonclinical

and

Clinical Studies,

March

2008

*

Good

Laboratory

Practices

Regulations

(21

CFR

§

58)

*

ISO

10993-1,

Biological

Evaluation

of

Medical Devices:

Evaluation

and

Testing

(2003)

The

biocompatibility

studies

are

summarized

in

Table

4.1

and

4.2.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

7

Table

4.1:

Biocompatibility

Test

Summary

(Stent

Test

/

Applicable

ISO

10993

Part

No.

Test Article

Test

Result

Cytotoxicity

(L929

MEM

Elution)

/

Part

5

Uncoated

Element

Stent

Pass

Cytotoxicity

(Direct

Contact)

/

Part

5

Uncoated

Element

Stent

Pass

Sensitization

(Guinea

Pig

Maximization)

/

Part

10

Uncoated

Element

Stent Pass

Intracutaneous

Reactivity

/

Part

10

Uncoated

Element

Stent

Pass

Acute

Systemic

Toxicity

/

Part

11

Uncoated

Element

Stent

Pass

Material-Mediated

Pyrogenicity

(Rabbit)

/

Part

11

Uncoated

Element

Stent

Pass

14

day

Repeat

Dose

Intravenous

Toxicity

/

Part

11

Uncoated

Element

Stent

Pass

13-week

Systemic

Toxicity

following

Uncoated

Element

Stent

13-weekControl:

Uncoated

Pass

Subcutaneous

Implantation

in

Rats

/

Parts

6

and

11

Exprss

Ute

Express

Stent

Ames

Mutagenicity

/

Part

3

Uncoated Element

Stent

Pass

In

vitro

Mouse

Lymphoma

/

Part

3

Uncoated

Element

Stent

Pass

In

vivo

Mouse

Micronucleus

/

Part

3

Uncoated

Element

Stent

Pass

Hemolysis

(Direct

Contact)

/

Part

4

Uncoated

Element

Stent

Pass

Hemolysis

(Extract Method)

/

Part

4

Uncoated Element

Stent

Pass

Complement

Activation

(C3a and

SC5b-9)/

Part

4

Uncoated Element

Stent

Pass

Supportive

Analytical

Chemistry

Tests

Chemical

Characterization

(Extractables

-

ICP

Uncoated

Element

Stent

Pass

Analysis)

Chemical

Characterization

(Residuals

and Uncoated

Stent

Pass

Leachables)

IONTM

and

Chemical

Characterization

(Corrosion

Challenge)

Unoad

Pass

Uncoated

Element

Stent

Since

the

applicant

did

not conduct

the

traditional

battery

of

ISO

10993

testing

on

the

finished

IONTM

stent

(i.e.,

containing

the

drug substance

and

coating);

sub-chronic

toxicity, in

vivo

thrombogenicity,

and

implantation

of

the

final

IONTM

stent,

containing

all

components

and

processing

were

evaluated

in

a

porcine

model

of

stent-mediated

vascular injury.

See

a

summary

of

this

study

in

Section

H

-

Animal Studies,

below.

Chronic

toxicity

and

carcinogenicity testing

of

the

IONTM

stent

was

not

conducted

because:

*

The

chemical

composition

of

the

Platinum Chromium Alloy

is

known

and

material

characterization testing

conducted

for the

bare

Element

Stent

demonstrated

that the

types

and

quantities

of

residues

or

leachables

present

from the

finished stent

do

not

raise

concerns for chronic

toxicity

or

carcinogenicity.

*

Paclitaxel

safety

has

been

extensively

studied.

The

concentration

of

paclitaxel

(1

tg/mm

2

)

and

the

amounts

used

in

this

application

are

equivalent

to

the

concentrations

used

in

the

approved

TAXUS

Express

2

(P030025)

and

TAXUS

Libert6

(P060008) stents;

therefore,

the

assessment

of

chronic

toxicity

and

carcinogenicity

provided

for

those

products

are

directly

applicable

to

the

IONTM

product.

*

The

SIBS

coating

process

and

amount

is

equivalent

to

that

used

in

the

approved

TAXUS

Liberte (P060008)

stents;

therefore,

the

assessment

of

chronic

toxicity

and

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

8

carcinogenicity

provided

for

that

product

is

directly applicable

to

the

IONTM

product.

Table

4.2:

Biocompatibility

Test

Summary

(Deliv

ry

Systems)

Test

/

Applicable

ISO

10993

Part

No.

Test Article

Rest

Result-

.

IONTM

MR

and

OTW

SDS

Cytotoxicity

(L929

MEM

Elution)

/

Part

5

(Cattr

p

nt

Pass

(Catheter

plus

stent)

PROMUS

Element

MR

Pass

Cytotoxicity

(Direct

Contact)

/

Part

5

SDS

(Catheter

only)'

ION

TM

OTW

SDS

Pass

(Catheter

only)

Sensitization

(Guinea

Pig

Maximization)

/

Part

10

ION

TM

MR

and

OTW

SDS

Pass

(Catheter

plus

stent)

Intracutaneous Reactivity

/

Part

10

IONTMMR

and OTW

SDS

Pass

(Catheter plus stent)

Acute Systemic

Injection

/

Part

11

ION

TM

MR and OTW

SDS

Pass

(Catheter plus

stent)

Material-Mediated Pyrogenicity (Rabbit)

/

Part

11

IONTMMR

and

OTW

SDS

Pass

(Catheter plus

stent)

Hemolysis (Direct Contact

/

Part

4

ION

TM

MR

and

OTW

SDS

Pass

(Catheter plus

stent)

PROMUS

Element

MR

Pass

.

SDS

(Catheter

only)'

Hemolysis

(Extract)

/

Part

4 SDS

IONTM

OTW

SDS

Ps

(Catheter

only)

Complement

Activation

(C3a and

SC5b-9)

/

Part

4

ION

TM

MR

and OTW

SDS

Pass

(Catheter

plus stent)

Supportive

Analytical

Chemistry

Tests

.

.110T

MR

and OTW

SDS

USP

Physicochemical

Test

for

Plastics

/

Part

18

j

MR

p

nt ]

Pass

(Catheter plus

stent)

'The

PROMUS

Element

and

IONTM

Monorail

delivery

catheters

consist

of

the

identical

materials

and

similar

processing,

and

data

provided

support

that

any

differences

will not

affect

the

biocompatibility

of

the

final

product.

Therefore

the

data

from

the

PROMUS

Element

Monorail

testing

are

applicable

to

the

IONTM

Monorail

device.

The

applicant

did not

conduct traditional in

vivo

thrombogenicity

on the

IONTM

MR

and

OTW

delivery

systems.

The

potential

for

thrombogenicity

was

evaluated

in

a

porcine model

of

stent

mediated

vascular

injury.

See

a

summary

of

this

study

in

Section

H

-

Animal studies, below.

Use

of

the

vascular implant

study

in

the

porcine

model

was

deemed acceptable because

the

materials

of

manufacture,

design,

and

processing

methods

for

the delivery

system

are

equivalent

to

the

approved

Apex

balloon

catheter

(P860019/SO28).

The

handle

of

this

delivery

system

incorporates

nanotechnology.

Detailed

manufacturing

information

and

material

characterization

and

biocompatibility testing

were

provided

to

confirm

that

there

is

no

release

of

nanoparticles

from

the

handle

of

this

device.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

9

Based

on the

testing

performed

for the

Element

stent

and

delivery

systems,

as

well

as

the

established

biocompatibility

and

safety data

on

paclitaxel

and

SIBS, it

can

be

concluded

that

IONTM

Coronary

Stent

System

is

biocompatible

for

its

intended

use.

B.

In

Vivo

Pharmakokinetics

B1.

ION

Paclitaxel-Eluting

Platinum Chromium

Coronary

Stent

Boston

Scientific has

provided

a

letter

from

the

drug

substance

manufacturer

authorizing

access

to

a

Drug Master

File

(DMF)

in

support

of

this

application.

The

drug

substance

manufacturer

produces

a

generic

form

of

the

drug

Taxol

,

a

Bristol

Myers

Squibb

drug

product that

is

approved

for

injection

of

multiple oncologic

indications.

In

vivo

animal

and

in

vitro

pharmacology

and

toxicology

studies,

as

well

as

in

vivo

animal

and

human

pharmacokinetic

studies,

were

conducted

on Taxol

to

provide

information

about

systemic, regional

and

local

toxicity, dose-related toxicity,

distribution

profiles,

end-

organ

disposition,

drug

metabolism,

and

potential drug-drug interactions.

Given

that

the

polymer

coating

and drug

component

of

the

ION

is

identical

to

that

of

the

TAXUS

Express

2

(P030025)

and

TAXUS

Libert6

(P060008), the

evaluation

of

TAXUS

Express

2

and

TAXUS

Libert6

is

applicable.

In

the

clinical

studies

TAXUS

1,

11,

and

III

(which evaluated

TAXUS8 Express

2

@)

and

ATLAS

(which

evaluated

TAXUS

Libert6),

no

paclitaxel

levels

were

detected

after

stent

implantation

using

an

analytical

method

with

a

lower limit

of

quantification

(LLOQ)

of

10

ng/ml.

These

findings

were

confirmed

in

preclinical studies using

multiple

stents

with

total

loaded doses above

the

clinically available

stent

system

and

an

assay

with

an

LLOQ

of

0.03

ng/ml.

Hence,

in

the

absence

of

systemically

detectable

levels,

standard

pharmacokinetic

parameters

were

not established.

B2.

Drug

Interactions

Paclitaxel

is

metabolized

in

the

liver via

CYP2C8

to

6-alpha-hydroxypaclitaxel

and

via

CYP3A4

to

3'-p-hydroxypaclitaxel

and

6-alpha,

3'-p-dihydroxypaclitaxel.

Paclitaxel

is

a

substrate

of

P-glycoprotein.

Because

metabolism

appears

to

play

an

important

role

in

the

elimination

of

paclitaxel,

agents

that

could compete

with

or

inhibit

the

CYP2C8 and

CYP3A4 isoenzymes

may

increase

paclitaxel

plasma

levels.

Potential

drug

interactions

may occur

with

any

drug

that

affects

these

isoenzymes.

Formal

drug

interaction

studies have not been

conducted with

the

ION

stent.

Consideration should

be

given

to

the

potential

for

both

systemic and

local

drug

interactions

in

the

vessel

wall

when deciding

to

place

an ION

stent

in

a

patient

who

is

taking

a

drug

with known

interactions

to

paclitaxel

or

when

deciding

to

initiate

therapy

with

such

a

drug in

a

patient

that

has

recently received

an

ION

stent.

C.

In

Vitro

Engineering

Testin2

In

vitro

engineering

testing

on

the

ION

Stent

System

was

conducted,

as

applicable,

in

accordance

with:

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

10

*

FDA

Guidance

for

Industry

and

Staff:

Non-Clinical

Tests

and

Recommended

Labeling

for

Intravascular

Stents

and

Associated

Delivery

Systems,

January

13,

2005,

*

FDA

Draft

Guidance

for

Industry and

Staff:

Coronary

Drug-Eluting

Stents

-

Nonclinical

and

Clinical

Studies,

March

2008,

and

*

FDA

Guidance

for

Industry

and

Staff:

Establishing

Safety

and

Compatibility

of

Passive

Implants

in

the

Magnetic

Resonance

(MR)

Environment,

August

2008.

In

vitro

engineering

testing

was

performed

on

the

ION

stent

mounted

on

either

the

MR

or

OTW

delivery catheters.

The

in

vitro

engineering

studies

conducted

are

summarized

in

Table

5

"Pass" denotes

that

the

test

results

met

product

specifications

and/or

the

recommendation

in

the above-

referenced

guidance

documents.

Additional

testing was

conducted

to

support

the

integrity

of

the

coating

on

the

IONTM

stent

as

shown

in

Section

IX

D

-

Drug

Coating

Characterization

Testing.

Table

5:

Stent

and

Delivery

Catheter

Engineering

Testing

1

Test

Test Description of Test

Rest

Results

Stent

Dimensional

and

Functional

Attributes

Material

Chemical

analysis

was

conducted

on

the

Platinum

Chromium

Pass

Composition

(PtCr)

ingot

provided

by

the

material

supplier

to

confirm

both

chemical

analysis

and

inclusion/impurity

content

as

provided

by

ASTM

F138-00

"Standard Specification

for

Wrought

18

Chromium-14

Nickel-2.5 Molybdenum Stainless

Steel

Bar and

Wire

for

Surgical

Implants

(UNS

S31673)."

The

analysis

confirmed that

the

chemical

composition

matched

the

ASTM

standard.

Stent

Corrosion

ION

stents were

tested

according

to

ASTM

F2129-01

"Standard

Pass

Resistance

Test Method

for

Conducting

Cyclic

Potentiodynamic

Measurements,"

ASTM

F756,

ASTM

G-71

to

Determine

the

Corrosion

Susceptibility

of

Small

Implant

Devices"

to

demonstrate

that

the

finished

stents

exhibit

acceptable

breakdown,

repassivation,

and

galvanic

coupling corrosion characteristics.

The

results

indicated

that

the

corrosion

resistance met

product specification.

Testing

also

included

an

assessment

of

Fretting

Corrosion

after

pulsatile

fatigue

cycling.

The

results

demonstrated that

there

was

no

evidence

of

fretting

corrosion

with

ION

stents

under

overlapping,

bent,

pulsatile

fatigue

conditions

up

to

400

million

cycles.

Dimensional

To

measure

and

inspect

the

substrate

(uncoated)

Element

stent

to

Pass

Verification document

that

the

un-expanded

stent

dimensional

specifications

meet

the

product

design

requirements.

All

products

met

specifications.

Percent

Surface

Stent

surface

coverage

as

a

function

of

stent

diameter

was

measured

Pass

Area

for the

IONTM

stent.

The

percent

surface

area

is

determined

by

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

11

dividing

the

measured

total

contact

surface

area

of

the

coated

stent

by

the

surface

area

of

the artery

based

on

deployed

stent

measurements

at

the

nominal

stent

diameter.

The

calculated

percent

surface

area

of

the

stent

should

be

<23.9%

when expanded

to

the

lowest

labeled

diameter.

Values

were

calculated

for

2.00

to

4.00

mni stent

diameters.

Foreshortening

The

lengths

of

the

stents

were

measured

prior

to

and

after

Pass

expansion

to

nominal diameter.

All

stents

met

product

specifications.

Recoil

for

Testing

was

conducted

to

quantify

the

amount

of

elastic

recoil

for

Pass

Balloon

the

stent

and

correlate

this

parameter

to

the

recommended

sizing

Expandable

procedures.

Results

indicated

that

product

specifications

were

met.

Stents

Stent

Testing

was

conducted

to

determine

whether

the

deformation

Pass

Overexpansion

experienced

by

the

stent

undergoing expansion

above

the

maximum

rated

diameter

gives rise

to

stent

or

coating

fractures.

No

stent

exhibited

any strut fracture

or

indications

of

coating integrity

issues

when

visually

examined

at

32X

following

over-expansion..

Radial

Stiffness Testing was

conducted

to

determine

the

ability

of

the

IONTM

stent

Pass-

and

Radial

to

resist deformation

under

radial

loads.

Strength

Compression

Testing

was

conducted

to

determine

the

radial

resistance

of

the

Pass

Resistance

IONTM

stent

to

external

compression.

Mechanical

Ultimate tensile

strength, yield strength

and

elongation

testing

was

Pass

Properties performed

on

tubing (pre-processing)

used

to

fabricate

the

stents.

Ultimate tensile

strength,

yield

strength

and

elongation

on

pre-

processed tubing

met

product specification. Analysis

of

SEM

images

on

stent

components

at

various

process

stages

determined

that

mechanical properties

were

not altered

by

processing.

Magnetic

The

ION

Stent

has

been shown

to

be

MR

Conditional

(poses

no

Pass

Resonance

known

hazards under

specified

conditions) through non-clinical

Imaging

(MRI)

testing

of

single

and

overlapped configurations

up

to

74

mm

in

Safety

and

overall

length.

The

conditions

are

as

follows:

Compatibility

*

Field

strengths

of

1.5

and

3

Tesla

*

Static

magnetic

field

gradient

<

9

T/m

(extrapolated)

*

Normal

operational

mode

(maximum

whole

body

averaged

specific

absorption

rate

(SAR)

of

lower

than

2.0

W/kg)

for

a

total

active

MR

scan

time

(with

RF

exposure)

of

15

minutes

or

less

The

ION

Stent should

not

migrate

in

this

MRI

environment.

MR

imaging

within

these

conditions

may

be

performed

immediately

following

the

implantation

of

the

stent.

This

stent

has

not

been

evaluated

to

determine

if

it is

MR

Conditional

beyond

these

conditions.

3.0

Tesla

Temperature

Information

Non-clinical

testing

of

RF-induced

heating

was

performed

at

123

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

12

MHz

in

a

3.0

Tesla

Magnetom

Trio®,

Siemens

Medical

Solutions

MR

system, software

version Numaris/4,

Syngo®

MR

A30.

RF

power

was

applied

for

15

minutes

and

the

measured conductivity

of

the

phantom

material

was about

0.3

S/m.

The

phantom

average

SAR was

calculated

using

calorimetry

to be 2.2

W/kg.

The

maximal

in-vitro temperature

rise

was

calculated

as

2.6

0

C

for

a

measured

stent

length

of

74

mm

with

the

whole-body

SAR

scaled

to

2.0

W/kg.

The

calculations

did

not

include

the

cooling

effects

due to

blood

flow.

1.5

Tesla

Temperature

Information

Non-clinical

testing

of

RF-induced heating

was

performed

at

64

MHz

in

a

1.5

Tesla

Intera®

Philips

Medical

Systems,

software

version

Release

10.6.2.0,

2006-03-10

whole

body

coil

MR scanner.

RF

power

was applied

for

15

minutes

and

the

measured

conductivity

of

the

phantom

material

was

about

0.3

S/m.

The

phantom

average

SAR

was

calculated

using

calorimetry

to

be

2.1

W/kg.

The

maximal

in-vitro

temperature

rise

was calculated

as

2.6

0

C

for

a

measured

stent length

of

74

mm

with

the

whole-body

SAR scaled

to

2.0

W/kg.

The

calculations

did

not

include

the

cooling effects

due to

blood

flow.

In

vivo,

local

SAR depends on MR Field

strength

and

may

be

different

than

the

estimated

whole body averaged

SAR,

due

to

body

composition,

stent

position

within

the

imaging

field,

and

scanner

used,

thereby

affecting

the

actual

temperature

rise.

Image

Artifact

Information

The

calculated

image

artifact extends

approximately

7

mm

from

the

perimeter

of

the

device

diameter

and

5

mm beyond

each

end

of

the

length

of

the

stent when

scanned

in

non-clinical

testing

using

a Spin

Echo

sequence.

With

a

Gradient

Echo

sequence

the

calculated

image

artifact

extends

5

mm

beyond

the

perimeter

of

the

diameter

and

6

mm

beyond

each

end

of

the

length with

both sequences

partially

shielding

the

lumen

in

a

3.0

Tesla Intera (Achieva

Upgrade),

Philips

Medical

Solutions,

software

version

Release

2.5.3.0

2007-09-28

MR system with

a

transmit/receive

head

coil.

Medical

Registration

It

is

recommended

that

patients

register

the

conditions

under

which

the

implant

can

be

scanned

safety

with

the

MedicAlert Foundation

(www.medicalert.org)

or

equivalent

organization.

Radiopacity

Testing

was

conducted

on

the

bare

metal

stent

as

the

addition

of

the

Pass

coating

did not

add

or

detract

from

the

radiopacity

of

the

stent

in

clinical

use.

Stent

Delivery

System

Dimensional

and

Functional

Attributes

Delivery,

The

delivery,

deployment

and

retraction

of

the

IONTM

Stent System

Pass

Deployment

was

assessed

by

testing

system

track, crossing

profile,

stent

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

13

and

Retraction

deployment,

guidewire

movement

and

balloon

withdrawal

from

a

stent

and into

the guide

catheter. Testing

demonstrated that

the

IONTM

stent

system

could

be

delivered

to

the

target

location,

deployed,

and

retracted,

thus

meeting required

product

specifications.

Balloon

Rated

IONTM

Stent Systems

were

tested

to

failure

to

demonstrate that

the

Pass

Burst Pressure

stent system met rated

burst

pressure.

All

stent

systems

met

(RBP)

specification

and

demonstrated

with

95%

confidence

that

at

least

99.9%

of

balloons

will

not experience loss

of

integrity

at

or below

the

rated

burst pressure.

Balloon

Fatigue

IONTM

Stent Systems across

the range

of

stent/balloon

lengths

and

Pass

diameters

were

required

to

complete

10

pressurization

cycles

to

Rated

Burst

Pressure

(RBP).

The

results

show

statistically

that,

with

95%

confidence,

90%

of

the

catheters

will

not

experience

balloon,

shaft,

or

proximal/distal

seal

loss

of

integrity

at

or

below

the

maximum

recommended

rated

balloon burst pressure.

Stent

Diameter

Testing

was

performed

to

determine how

the

diameter

of

a

deployed

Pass

vs.

Balloon stent

varies

with applied

balloon

pressures.

The

stent

sizing

results

Pressure

verify

that

the

stent

systems

meet

the

labeled

compliance values.

Catheter

Bond

Representative

sizes

of

the

IONTM

stent

delivery system

were

tested

Pass

Strength

to

determine

the

balloon

bond

and

full

unit tensile strength

of

the

delivery

system.

All

stent systems exceeded

the

minimum

specifications

for

full

unit tensile

strength

and

balloon

bond.

Balloon

IONTM

delivery systems

across

the

range

of

balloon

lengths

and Pass

Deflation

Times

diameters

were

tested

for

deflation

times,

and

all

stent

systems

met,

specifications.

Stent

Testing was

conducted

to

assess

the forces

required

to

displace

a

Pass

Securement

for

crimped

IONTM

stent

from

the

delivery

systems

(1)

directly

from

the

Unsheathed

balloon

catheters,

(2)

after tracking

through

a

simulated

tortuous

Stents

artery

model

and

(3)

after

tracking

through

a

simulated tortuous

artery

model

and

then

through

a

simulated lesion.

All

stent systems

met

the

stent

securement specification.

Non-Coaxial Testing consists

of

withdrawing

a

catheter with

a

mounted

stent non-

Pass

Withdrawal

into

coaxially

into

a

simulated

guide

catheter

tip,

at a

45oC

angle,

a

Simulated

following

a

track

conditioning

step,

in

which

the

IONTM

Stent

Guiding

Delivery Systems

were

challenged

by

repeatedly

tracking

the

Catheter

crimped stent system

three

(3)

times

through

a

tortuous

artery

model.

The

unit

was

then

assessed

for

stent

movement.

All

samples met the

product

specification.

Balloon

Testing

was

conducted

to

verify

that

the

IONTM

stent

system

can

be

Pass

Catheter

safely

withdrawn

back into

the

recommended

guide

catheter

sizes

Withdrawal

both

before and

after

stent

deployment.

All

samples met

the

product

Resistance

specification.

Coating

The

coating

durability

of

the

IONTM

stent

coating

was

assessed

via

a

Pass

Durability

series

of

acute

in

vitro

tests

performed

on

the

coated stent

and

the

SIBS

polymer.

The

test

results

demonstrate

that

the

paclitaxel/SIBS

coating displays

good

durability

and

coating

integrity.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

14

Coating

Adhesion

and

Cohesion

testing

has

been

performed

to

Pass

Adhesion

and

.

assess

the

adhesive

and

cohesive

properties

of

the

IONTM

stent

Cohesion

coating.

The

IONTM

coating demonstrates

adequate

adhesion

and

cohesion properties.

The

coating

has

a

high

resistance

to

detachment

from

the

stent

and

is

therefore

considered

acceptable

for

intended

use.

Stress

and

Using Finite

Element

Analysis

(FEA),

stress

and

strain

analysis

was

Pass

Strain

Analysis

performed

on

the

stent

and

the

stent coating

to

demonstrate.

that

they

(Finite

Element

maintain

acceptable

safety

in

stress

loading

environments,

Analysis

simulating

nominal

and

overexpansion,

and

bending

and

radial

(FEA))

conditions.

The

FEA

evaluated

the

structural

integrity

of

the

stent

and

coating

when subjected

to

the

expected

loading

conditions

generated

in

coronary

arteries.

The

analysis

took

into

account

manufacturing,

delivery,

implantation

and

clinical

loading over

the

implant

life,

and

predicted

that

fatigue

failures

will

not

occur

over

400

million

cycles

(10-years)

of

loading.

Accelerated

durability

testing

was

performed

on the

IONTM

stent

and Pass

Durability

the

stent coating

to

demonstrate

that

the

structural integrity

and/or

Testing coating

integrity

is

maintained following

exposure

to

the

pulsatile

stresses

and

strains

exceeding those

typically experienced

by

a

human

coronary

artery

for

10

years (400

million

cycles).

Testing

included

assessment

of

Post-Elution

Fatigue

and

Overlapping

Pulsatile

Fatigue

on

a

Curve

(PFC).

All

tested

stents

were

free from

fatigue

induced

surface defects,

and

there

was

no

evidence

of

coating

fatigue

or

corrosion.

The

stent met the

10

year accelerated

fatigue

resistance

requirement

of

the

product specification.

The

overlapping

stents

were

also

evaluated

in

an

accelerated

in

vitro

test

of

approximately

10

year

equivalent

real

time

and

met

visual

requirements

for coating integrity

and

strut

damage.

Particulate Particulate

testing

has been

performed

on the

IONTM

stent

system

in Pass

Testing accordance

with

the

recommendations

in

the

draft

FDA

Guidance

for

Industry:

Coronary Drug-Eluting

Stents

-

Nonclinical

and

Clinical Studies,

March

2008,

including

revisions presented during

the

2008

Transcatheter Cardiovascular Therapeutics (TCT)

Conference,

Washington

DC,

October

15,

2008.

Testing

included

assessment

of

Baseline Particulate

(Overexpansion), Simulated

Use

Particulate,

and

Chronic Particulate

(Pulsatile

Particulates

in

a

Curve

(PPC)).

The

results demonstrate that

the

particulate

counts

are

similar

or

lower

for

IONTM

coated

stents

compared

to

bare

Element

stents.

Given

comparable particulate

counts, and

that

there

is

no

evident

increase

in

counts

on

IONTM

coated stent

product,

no

chemical

identification

of

particulates

was

warranted.

D.

Drug

Coating

Characterization

Testing

The

coating

characterization

testing

conducted on

the

ION

stent

coating

is

summarized

in

Table

6.

PMA

P100023:

FDA

Summary

of

Safety and

Effectiveness

Data

Page

15

Table

6:

Coating

Characterization

Testing

Test

Description

of

Test

Polymer

components

were

tested

to

ensure

conformity

to

raw

material

Polymer

specifications

and

incoming

inspection

procedures.

The

analysis

confirmed

the

material

met specifications.

Assays

were

conducted

to

determine

Mw,

Mn,

polydispersity,

Chemical

Analysis-

monomer

content,

presence/formation

of

oligomers,

and

free

Polymer

monomers.

The

results

of

each

assay

met

specifications

established

by

the

applicant.

Chemical

Analysis

-

Drug

substance

was

tested

to

ensure

conformity

to

incoming

Certificate

Drug

of

Analysis

(COA);

the

testing

confirmed

conformity

to

the

COA.

Assay

was

conducted

to

quantitatively

determine

the

total

amount

of

Drug

Content

the

drug

substance,

paclitaxel,

on

the

ION

stent.

The

results

verified

that samples

met

the

targeted

drug

content specifications.

Dose

Density

Dose

per

unit

area

was

calculated.

C

n

UTesting

was

conducted

to

verify

the

reproducibility

of

coating

t

uniformity

from

stent

to

stent

and

batch

to

batch.

Testing confirmed

Reproducibility.

.

adequate

coating

uniformity/reproducibility

as

outlined

in USP

<905>.

Assays

were

conducted

to

quantitatively determine

the

type

and

Impurities/Degradation

amount

of

impurities

and

degradation products

on the

ION

stent.

Products

Testing confirmed

acceptable

levels

of

impurities

and

degradation

products.

Assay

was

developed

to

measure

the

in

vitro

release

kinetics

of

In

vitro

Elution

paclitaxel

off

the

ION

stent.

An appropriate

method

and

specifications

were

developed

for

this parameter.

Particulate

levels

were

evaluated

for the

ION

stent system

under

Particulates

simulated

use

conditions,

including

tracking

and

deployment

(see

Table

1

5

above).

E.

Chemistry,

Manufacturing,

and Controls (Quality)

Testing

Samples

from

each

batch

of

finished

stents

are

subjected

to

certain

tests

prior

to

release.

This

testing

is

summarized

in

Table

7.

Where

applicable,

the

test

methods

follow

International Conference

on

Harmonization

(ICH)

Guidelines. Information

to

support

the

stability

of

ION

is

summarized

separately

in

Section

IX

F

-

Stability

below.

Table

7:

ION

Stent

Release

Testing

Test

Description

of

Test

Material

Analysis

-

The

polymer

was

tested

to

ensure

conformity

to

specifications.

The

Polymer

polymer

met

specifications

prior

to

utilization

in

finished

goods.

Assay

is

conducted

to

verify

the

identity

of

the

drug

substance,

paclitaxel,

in

the

ION

stent.

Drug

Assays

are

conducted

to

quantitatively

verify

the

amount

of

drug

and

the

Content/Impurities

type

and

amount

of

impurities

on

the

ION

stent.

Drug

Content

Multiple

stents

are

assayed

to

verify

the

uniformity

of

the

drug

content

Uniformity

between

individual

stents

is

within

specifications

established

for

the

ION

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

16

Table

7:

ION

Stent

Release

Testing

Test

Description

of

Test

stent.

In

vitro

Drug

Elution

The

in

vitro

release

profile

of

paclitaxel

is

measured

to

verify

that

the

drug

release

is

within

the

specifications

established

for

the

ION

stent.

Particulates

Particulate

counts

are

measured

to

verify

that

they

remain

below

acceptable

levels

established

for

the

ION

stent.

F.

Stability

studies

specific

to

the

polymer/drug

coating

component

were

conducted

in

accordance

with

ICH

guidelines

to

establish

a

shelf

life/expiration

date

for

the

ION

stent

system.

In

addition,

testing

to

establish

package integrity

and

functional

testing

of

the

stent

and

delivery

system

were

conducted

on aged

product

to

ensure that

ION

continues

to

meet

specifications

throughout

its

shelf

life.

The

data

generated

support

a

shelf

life

of

18

months.

Stability studies

included

evaluation

of

drug

identity,

assay,

degradants,

in

vitro

elution, particulates,

sterility,

drug

content uniformity,

residual solvents,

and

endotoxin.

In

addition,

the stability

of

the

drug

substance

and

inactive

polymer

has

been

independently

verified.

G.

Sterilization

The

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent System

(Monorail

and

Over-The-Wire)

is

sterilized

using

ethylene

oxide sterilization and

has

been validated

per

AAMI/ISO

11135:1994 "Medical

Devices

-

Validation

and

Routine

Control

of

Ethylene

Oxide

Sterilization."

Results

obtained

from the

sterilization

studies

show

that

the

product

satisfies

a

minimum

Sterility

Assurance

Level

(SAL)

of

10-6.

The

amount

of

bacterial

endotoxin

was

verified

to

be

within

the

ANSI/AAMI

ST72

specification limit

or

ION

stent

delivery

systems.

H.

Animal Studies

Because

detailed

arterial

histopathology

and

histomorphometry

and

pharmacokinetic

data

cannot

be

obtained

through

human clinical

trials,

a

series

of

animal

studies

were

conducted

to

evaluate safety,

vascular compatibility,

in

vivo drug release, and acute

product

performance.

The

safety,

vascular

compatibility,

and

acute

performance

of

ION

paclitaxel-eluting

stents

were

evaluated

in

the

non-injured

porcine

coronary

artery

model. Studies

were

conducted

in

accordance

with

§21

CFR

58

(Good

Laboratory Practices).

The

consistency

of

the

vascular

response

to

the

Element

platform

with

the

approved

Libert6

platform

was

evaluated

and

compared

in

the

Overlap

ION

Study

1133-024.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

17

Acute

performance

of

ION

was

evaluated

in

Study

1133-027.

ION

in

vivo

paclitaxel

release

and

tissue

paclitaxel

levels

were

evaluated

and compared

with

TAXUS8

Express20

in

Study

BJAOO

172

using

the

rabbit

iliac

artery

model.

The

results

of

these

tests

support

the

safety

and

vascular

compatibility

of

the

ION

Stent.

Summaries

of

these

studies

are

included

in

the

Tables

8

through

10

below.

Table

8:

Summary

of

the

Porcine

Overlap

Slow

Release

(8.8%)

ION

Study:

1133-024

Dose

Density,

Target

#

Stents/

Vessel

Evaluation

Testing

Stent

Model

Release

Stent

Size

Animal

Formlaton

#Anials

Location

Time

Points

Objective

Formulation

#

Animals

I

ig/mm

2

2.75

x

12

1

overlap

ION

Slow

Release

pair/animal

Establish

(8.8%)

39

animals

safety

of

I

overlap

small

Uncoated

N/A

2.75

x

12

pair/animal

workhorse

Element

NAmm

pair/nima

39

animals

LAD,

30,

90,

and

stents.

TAXUS

1

Ig/mm

2

2.75

x

12

1

overlap

RCA,

LCX

180

days

Mortality,

Libert6

Slow

Release

mm

pair/animal

morphology,

Controls

(8.8%)

39

animals

morphometry,

Uncoated

I

overlap

myocardial

Libert6

N/A

2.75

x

12

pair/animal

effects

Controls

mm

39

animals

Table

9:

Summary

of

the

Porcine

Acute

Performance

ION

Study:

1133-027

Dose

Density,

Target

#

Stents/

Vessel

Evaluation

Testing

Stent

Model

Release

Stent

Size

Animal

Formlaton

UAnials

Location

Time

Points

Objective

Formulation

#

Animals

2

Establish

ION

Slow

Release

3.0

x

8mm

2

animals

h

g

Acute

18

42.5

x

8mm

6or

l

LCX

performance

(8.8%)

4.0

x

8mm

of

stents.

Table

10:

Summary

of

the

Rabbit

In

Vivo

Release

Slow

Release

(8.8%)

ION

and

TAXUS

Express

2

Study:

BJA00172

Dose

Density,

Target

#

Stents/

Vessel

Evaluation Testing

Stent

Model

Release

Stent

Size

Animal

Formlaton

UAnials

Location

Time

Points

Objective

Formulation

#

Animals

Compare

1

ig/

mm

2

Slow

2.5

x

12

1/animal

10,3045,

potential

ION

RIliac

artery

60, 90,

180,

local

Release

(8.8%)

mm

70

animalsan27Dysvcur

and 270

Days

vascular

paclitaxel

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

18

Dose

Density,

Target

#

Stents/

Vessel

Evaluation

Testing

Stent

Model

Release

Stent

Size

Animal

Formlaton

#Anials

Location

Time Points

Objective

Formulation

#

Animals

exposure

for

SR

Element

versus

SR

TAXUS

2.5

x

12

1/animal

Express

2

Express

2

mm

70

animals

using

stent

content

and

tissue

paclitaxel

levels.

IX.

SUMMARY

OF

PRIMARY

CLINICAL

STUDIES

The

applicant

collected

clinical data

through

the

PERSEUS

Clinical

Trial

Program,

to

establish

a

reasonable

assurance

of

safety

and

effectiveness

of

coronary

artery

stenting

with

the

ION

stent

for

improving

luminal diameter

for the

treatment

of

de

novo lesions.

The

PERSEUS

program

consisted

of

two

(2)

parallel studies,

PERSEUS

Workhorse

(WH) and

PERSEUS

Small

Vessel

(SV).

The

PERSEUS

WH

included

sites

in

the

United

States,

New Zealand,

Australia,

and

Singapore.

The

PERSEUS

SV

was

a

US-

only study. Both

trials

were

evaluated

under

IDE

G060237.

Data

from

this clinical

study

were

the

basis

for

the

PMA

approval

decision.

A

summary

of

the

clinical

study

is

presented

in

Table

11

below.

PERSEUS WH

The

PERSEUS

Workhorse

(WH)

study

is

a

prospective, randomized, controlled,

single-

blind, non-inferiority

trial

to

evaluate

the

safety and

efficacy

of

the

1 hg/mm

2

(loaded

drug/stent

surface area)

IONTM

Stent

in

the

treatment

of

de

novo

coronary lesions.

Subjects

with de

novo target

lesion length

<28mm and

target

vessel

diameter

>2.75mm

to

K4.Omm

were

considered

for

enrollment.

The

trial

employs

a

3:1

randomization

to

the

ION

or the

TAXUS

Express

Paclitaxel-Eluting

Stent

respectively.

The

primary

endpoint

is

the

rate

of

target

lesion failure

(TLF;

including

any

ischemia-

driven revascularization

of

the

target

lesion

[TLR],

myocardial

infarction

[MI;

Q-wave

and

non-Q-wave]

the

target vessel,

or

cardiac

death

the

target vessel)

at

12

months

post-index

procedure,

testing non-inferiority

of

the

ION

Stent relative

to

the

TAXUS

Express

Paclitaxel-Eluting

Stent

control.

In-segment percent diameter stenosis

at

9

months

post-index

procedure

as

measured

by

quantitative

coronary

angiography

(QCA)

is

the

secondary

endpoint.

Enrollment

of

1264

subjects

was

planned;

1262

(942

ION

Stent and

320

TAXUS

Express

Stent)

were

enrolled

and

randomized

at

90

sites.

A

total

of

330

subjects

were

randomly

assigned

to

protocol-mandated

9-month

angiographic follow-up

(angiographic subset).

The

protocol mandated

antiplatelet

therapy compliance

in

accordance

with

the

ACC/AHA/SCAI

Guidelines

for

PCI

2

.

The

study

is

now considered

complete with

regard

to

the 12-month

primary

endpoint.

Additional

follow-up

is

ongoing

to

5

years.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

19

PERSEUS

SV

The

PERSEUS

Small Vessel

(SV)

study

is

a

prospective,

single-arm,

superiority

trial

to

evaluate

the

safety

and

efficacy

of

the

1

tg/mm2

(loaded

drug/stent

surface

area)

2.25mm

and

2.5mm

IONTM

Stents

in

the

treatment

of

de

novo

coronary lesions

in

small

vessels.

Subjects

with

de

novo

target

lesion

length

<20mm

and target

vessel

diameter

>2.25mm

to

<2.75mm

in

a

native

coronary

artery

were

considered

for

enrollment.

The

trial

compares

the

ION

Stent

to

a

matched

bare metal

(Express

Stent)

historical

control

group

comprised

of

subjects

with reference vessel

diameter (RVD)

2.25 to

<2.75mm

and

lesion

length

20mm

from

the

TAXUS

V

trial.

The

TAXUS

V

trial

is

more

fully

described

in

the

SSED

for

P030025/SO28

(see

http://www.accessdata.fda.gov/cdrh

docs/pdf3/P030025SO28b.pdf).

All

subjects

in

PERSEUS

SV

were

required

to

undergo

a

9-month

angiographic

assessment.

The primary

endpoint

is

in-stent

late

loss

by

quantitative

coronary

angiography

(QCA)

on

9-

month

follow-up

(ION

Stent

compared

to

bare

metal

Express

Stent)

and

the

secondary

endpoint

is

TLF

at

12

months

(ION

Stent

compared

to

a

performance

goal

based

on

TAXUS

Express

Stent results from

the

TAXUS

IV

and

TAXUS

V

trials).

A

total

of

224

subjects

were

enrolled

at

28

sites. The

control

group

consisted

of

125

matched

bare

metal

Express

Stent

subjects from

the

TAXUS V

trial,

including

108

with

9-

month

QCA

follow-up.

The

protocol

mandated antiplatelet therapy compliance

in

accordance

with

the

ACC/AHA/SCAI

Guidelines

for

PCI

2

.

The

study

is

now considered complete with

regard

to

the

primary endpoint.

Additional

follow-up

is

ongoing

to

5

years.

Table

11:

Compari

on

of

PERSEUS

Clinical Studies

PERSEUS

Workhorse

PERSEUS

Small

Vessel

Purpose

Evaluation

of

safety

and

Evaluation

of

safety

and

effectiveness

in

workhorse

lesions

effectiveness

in

small

vessel

lesions

Prospective,

multicenter, Prospective,

multicenter,

single-

Study

Design

randomized, single-blind,

non-

arm,

superiority

to BMS

inferiority

to

PES

Primary

Endpoint

12-month TLF

9-month in-stent

late

loss

Total:

1264

planned;

1262

Total:

224

Number

of

Subjects enrolled

and

randomized

ION

Stent: 224

(ITT)

ION

Stent:

922

TAXUS

Express

stent:

320

Polymer

Slow

Release

Translute

m

Polymer

PTx

Dose

Density

1

gg/mm

Lesion

Criteria:

>2.75mm

to

<4.00mm

>2.25mm

to

<2.75mm

Vessel Diameter

(by

visual

estimate)

Lesion

Criteria:

Lesion

Length

(by

<28mm

<20mm

visual

estimate)

Number

of

stents

Single

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

20

Stent

Matrix

2.75-4.0mm

diameter

2.25-2.50mm

diameter

8,

12,

16,

20,

24,

28,

32mm

length

8,

12,

16,

20,

24mm

length

Post-Procedure

Clopidogrel

or

ticlopidine:

at

least

6

months,

ideally

for

12

months

in

Antiplatelet

subjects

who

are

not

at

high risk

for

bleeding.

Therapy

ASA:

indefinitely

Clinical:

30

day,

9

month,

1

year,

Clinical:

30

day,

9

month,

1

18

month,

annually

2-5

years

year,

18

month,

annually

2-5

Angiographic

(330

subject

subset):

years

9

month

Angiographic

(all):

9

month

Abbreviations:

ASA=aspirin;

BMS=bare

metal

stent;

ITT=intent-to-treat;

PES=paclitaxel-

eluting

stent;

PTx=paclitaxel;

TLF-target

lesion failure

POTENTIAL

ADVERSE

EFFECTS

OF

THE

DEVICE

ON

HEALTH

Below

is

a

list

of

potential

adverse

events

(in

alphabetical

order) which

may

be

associated

with

the use

of

a

coronary stent

in

native

coronary

arteries

including

but

are

not

limited

to:

*

Abrupt

stent

closure

*

Acute

myocardial

infarction

*

Allergic

reaction

to

anti-coagulant

and/or

antiplatelet

therapy,

contrast medium,

or

stent

materials

*

Angina

*

Arrhythmias,

including

ventricular

fibrillation

and

ventricular tachycardia

*

Arteriovenous

fistula

*

Cardiac

tamponade

*

Cardiogenic

shock/pulmonary

edema

*

Coronary

aneurysm

*

Death

*

Dissection

*

Emboli,

distal

(air,

tissue

or

thrombotic

material

or

material

from

devices(s)

used

in

the

procedure)

*

Heart

failure

*

Hematoma

*

Hemorrhage,

requiring transfusion

*

Hypotension/hypertension

*

Infection,

local

or

systemic

*

Ischemia,

myocardial

*

Pain,

access

site

*

Perforation

or

rupture

of

coronary artery

*

Pericardial

effusion

*

Pseudoaneurysm,

femoral

*

Renal

failure

*

Respiratory

failure

*

Restenosis

of

stented

segment

*

Stent

embolization

or

migration

*

Stent

thrombosis/occlusion

*

Stroke/cerebrovascular

accident

/TIA

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

21

*

Total

occlusion

of

coronary

artery

*

Vessel

spasm

*

Vessel

trauma

requiring

surgical

repair

or

reintervention

Potential

adverse

events

not

captured

above,

that

may

be

unique

to

the

paclitaxel

drug

coating:

*

Allergic/immunologic

reaction

to

drug

(paclitaxel

or structurally-related

compounds)

or

the

polymer

stent

coating

(or

its

individual

components)

*

Alopecia

*

Anemia

*

Blood

product

transfusion

*

Gastrointestinal

symptoms

*

Hematologic

dyscrasia

(including

leukopenia,

neutropenia,

thrombocytopenia)

*

Hepatic

enzyme

changes

*

Histologic changes

in

vessel

wall,

including

inflammation,

cellular

damage

or

necrosis

*

Myalgia/arthralgia

*

Peripheral

neuropathy

For

the

specific adverse

events

that

occurred

in

the clinical studies,

please

see

Section

IX,

Tables

13

and

20.

A.

PERSEUS

WH

Clinical

Trial

Primary

Objective:

The

primary

objective

of

the

PERSEUS

WH study

was

to

evaluate

the

safety

and

efficacy

of

the

IONM Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System

for the

treatment

of

de

novo

atherosclerotic lesions

of

up

to 28mm

in

length

(by

visual

estimate)

in

native

coronary

arteries

of

2.75mm

to

4.0mm

diameter

(by

visual

estimate)

compared

to

TAXUS

Express

Stent control.

Design:

PERSEUS

WH

is

a

prospective, randomized, controlled,

single-blind,

non-

inferiority trial

which employs

a

3:1

randomization

to

the

ION

or

the

TAXUS

Express

Paclitaxel-Eluting

Stent

respectively.

Eligible subjects

were

those

18

years

old with

documented

stable

angina

pectoris, unstable

angina pectoris,

or

documented

silent

ischemia

and

left

ventricular ejection

fraction (LVEF)

30%.

De

novo

target lesions

in

a

native coronary

artery

'with

diameter

stenosis

>50%,

reference

vessel diameter

>2.75mm

to

<4.0mm,

and

cumulative

lesion

length

<28mm

coverable

by

a single

study

stent

were

eligible.

Multiple

stenting

was

allowed

for

bail-out

only.

The

protocol

mandated

antiplatelet therapy compliance

in

accordance

with

the

ACC/AHA/SCAI

Guidelines

for

PCI

2

.

While subjects

in

this

trial

could

be

blinded,

the

operators

could

not,

as

the

identity

of

the

stent could

be

determined

by

the

operator on

the

basis

of

a

visual

comparison

of

stent

design prior

to

implantation.

Use

of

a

Clinical

Events

Committee

and

an

angiographic

core

lab

minimized

potential

bias

introduced

from

the

inability

to

completely

blind

all

study

participants.

Enrollment

of

1264

subjects was

planned.

A

total

of

1262

(942

ION

Stent and

320

TAXUS

Express

Stent)

were

enrolled

and

randomized

at

90

centers.

Of

the

1262

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

22

subjects

included

in

the

intent-to-treat

analysis

set,

a

total

of

1235

subjects

(922

ION

Stent

and

313

TAXUS

Express

Stent)

were

evaluable

for

the

12-month

primary

endpoint.

A

total

of

330

subjects

(256

ION,

74

TAXUS

Express)

were

randomly

assigned

to

protocol-mandated

9-month

angiographic

follow-up

(angiographic

subset).

Angiographic

assessments

were

performed

for

the

area

of

the

vessel

within

the

stent

margins

(in-stent)

and

the

areas

immediately

5

mm

proximal

and

distal

from the stent

margins

(analysis

segment).

An

angiographic

core

lab

was

utilized

for

analysis

of

angiography

data.

A

Clinical

Events

Committee

(CEC)

served

as

a

multidisciplinary

expert

group

responsible

for

the

independent

and

ongoing

adjudication

of

prespecified

clinical events,

including

all

reported deaths, myocardial

infarctions

(MI),

target vessel

revascularizations

(TVR),

and

stent

thromboses

(ST),

as

defined

by

the

clinical

protocol.

A

Data

Monitoring Committee

(DMC)

of

independent

experts

in

cardiology,

cardiovascular

interventional therapy,

and

biostatistics

worked

to

ensure

patient

safety

by

evaluating

accumulating

data

from

the

PERSEUS

Clinical

Program.

1.

Clinical

Inclusion

and

Exclusion

Criteria

Enrollment

in

the

PERSEUS

WH

study

was

limited

to

subjects

who

met

the

following

inclusion

criteria:

*

Subject

is

>

18

years

old

*

Eligible

for

percutaneous

coronary

intervention

(PCI)

*

Documented

stable

angina

pectoris,

or

documented

silent

ischemia

*

Acceptable candidate

for

coronary

artery

bypass

grafting

(CABG)

*

Left

ventricular

ejection

fraction

(LVEF)

is

>

30%

*

Subject

(or

legal

guardian)

understands

the

study

requirements

and

the

treatment

procedures

and

provides

written

Informed

Consent

before

any

study-specific tests

or

procedures

are

performed

*

Subject

willing

to

comply with

all

specified

follow-up evaluations

ANGIOGRAPHIC INCLUSION

(by

visual

estimate)

*

Target lesion

located

in

native coronary artery

*

Target

lesion

must

be

de

novo

*

Target lesion

diameter stenosis

>50%

*

Reference vessel

diameter

(RVD):

>2.75mm

to

<4.0mm

*

Cumulative

target

lesion

length (area

to

be

treated

must

be

completely

coverable

by

one

study

stent):

28mm

*

Target

lesion

is

successfully

pre-dilated.

Subjects

are

enrolled

only

after

successful

balloon catheter

pre-dilation

of

the

target

lesion

*

One

non-target

lesion

may

be

treated

in

a

non-target

vessel

*

Non-target

lesion

in

non-target

vessel

must

be

treated

with

a

commercially

available

TAXUS

stent

if

use

of

drug-eluting

stent

required

*

Treatment

of

a

non-target

lesion

(if

performed)

must

be

deemed

a

clinical

angiographic

success,

without

requiring

use

of

unplanned

additional stent(s)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

23

*

Treatment

must

be

completed prior

to

treatment

of

target

lesion

Subjects

were

not

permitted

to

enroll

in

the

PERSEUS

WH

study

if

they met

any

of

the

following

exclusion

criteria:

*

Contraindication

to

ASA,

or

to

both

clopidogrel

and

ticlopidine

*

Known

hypersensitivity

to

paclitaxel

*

Known

allergy

to

stainless

steel

*

Known

allergy

to

platinum

*

of

the

target

vessel

with

any

anti-restenotic

drug-

coated

or

drug-eluting

coronary

stent

*

Previous treatment

of

the

target

vessel

with

a

bare metal

stent

(BMS)

within

9

months

of

the

index

procedure

*

of

any

non-target

vessel with

any

anti-restenotic

drug-

coated

or

drug-eluting

coronary

stent

within

9

months

of

the

index

procedure

*

with

intravascular

brachytherapy

in

the

target

vessel

*

Planned

PCI

or

CABG

post-index

procedure

*

Planned

or

actual

target vessel

treatment

with

an

unapproved

device,

directional

or

rotational coronary

atherectomy,

laser,

cutting

balloon

or

transluminal extraction

catheter

immediately prior

to

stent

placement

*

Myocardial

infarction

(MI)

within

72

hours

prior

to

the

index

procedure

as

defined per protocol

definition

(see

Section

4.2)

*

Cerebrovascular

accident

(CVA)

within

the

past

6

months

*

Cardiogenic

shock

characterized

by

systolic

pressure

<80mm

Hg

and/or

central

filling pressure

>20mm

Hg,

or cardiac

index

<1.8

liters/minute/m

2

or

intra-aortic

balloon pump

or

intravenous inotropes

are

needed

to

maintain

a

systolic

pressure

>

80mm

Hg

and

a

cardiac index

>1.8

liters/minute/m

2

*

Acute

or

chronic

renal

dysfunction

(creatinine

>

2.0

mg/dl

or

177

jtmol/l)

*

Any

prior

true anaphylactic reaction

to

contrast

agents;

defined

as

known

anaphylactoid

or

other

non-anaphylactic

allergic

reactions

to

contrast agents

that

cannot

be

adequately pre-medicated prior

to

the index

procedure

*

Leukopenia

(leukocyte count

<3.5 x

109/liter)

*

Thrombocytopenia

(platelet

count

<100,000/mm

3

)

*

Thrombocytosis

(>750,000/mm3)

*

Active peptic ulcer

or

active

gastrointestinal

(GI)

bleeding

*

Current

treatment,

or

past

treatment

within

12

months

of

the

index

procedure,

with

paclitaxel

or

other

chemotherapeutic

agent(s)

*

Anticipated treatment

with

paclitaxel

or oral

raparmycin

during

any

period

in

the

9

months

after

the

index

procedure

*

Male

or

female

with

known

intention

to

procreate within

9

months

after

the

index

procedure

*

Positive pregnancy

test within

7

days

before

the

index procedure,

or lactating

*

Life

expectancy

of

less

than

24

months

due

to

other

medical

conditions

*

Co-morbid

condition(s)

that

could

limit

the

subject's

ability

to

comply

with

study

follow-up

requirements

or

impact

the

scientific

integrity

of

the

study

*

Currently

participating

in

another investigational

drug

or

device

study

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

24

ANGIOGRAPHIC

EXCLUSION

(by

visual

estimate)

"

Target

lesion

in

left

main

artery,

whether

protected

or

unprotected

*

Target

lesion

is

a

chronic

total

occlusion

(TIMI

flow

<1)

*

Target

lesion

is

restenotic

*

Target

lesion

is

located

in

a

saphenous

vein

graft or

mammary

artery

graft

*

Target

lesion

is

accessed

via

saphenous

vein

graft

or

mammary

artery

graft

*

Target

lesion

is

<5mm

from

bare

metal

stent

(BMS)

*

Target

lesion

is

<5mm

from

ostium

*

Target

lesion

is

<5mm

from

a

side

branch vessel

2.0mm

in

diameter

(Exceptions:

subject

may

be

enrolled

if

side

branch

is

100%

occluded

or

if

side

branch

is

protected

with

a

patent

graft)

*

Untreated

lesions

with

>50%

diameter

stenosis

or

thought

to

impair

flow

remaining

in

target vessel

at

a

location

with

2.0mm

RVD

*

Target

lesion

and/or target

vessel

proximal

to

the

target

lesion

is

moderately or

severely

calcified

*

Target lesion

and/or

target

vessel

proximal

to

the

target

lesion

is

severely

tortuous

*

Target lesion

is

located

within

or

distal

to

a

>600

bend

in

the

vessel

*

Target

lesion

with

angiographic

presence

of

probable

or

definite

thrombus

*

Unprotected

left

main

coronary

artery

disease

*

Protected

left

main

coronary

artery

disease

with

target

lesion

in

LAD

or

LCX

(subject

may

be

enrolled

if

only

lesion

is

target

lesion

in

RCA)

2.

Follow-up

Schedule

All

subjects

were

scheduled

to

return

for

follow-up examinations

at

30

days,

9,

12

and

18

months,

and

2,

3,

4

and

5

years

post

index

procedure.

Subjects

received

the

examinations

outlined

in

Table

12.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

25

6

ON 0

CD

K

JN

w

o

CD~

C)

0

-!

00

--

o-

-

CA, c~

0

a

<

00

0z

0

0-

<

0

>

CD9

0

CD

00

0

r,

D0

~0

-

nc

Eno

0<

a-

-t0

CD

~

0

V

--

IA

o

co

P

-0 0

a

0 S-

~

aD

0

oo

'o

a

00 x

a,

0

'=

0 r-

= .= 0j( F .

03~

-Da

C

-0

0.

-~

00-

CD

0

CDS

w

co

0

o

a

-

0

C

0

)0

W0 -

o

0

-

:a

N

(a.

0

oD

o

0-

n

o0a

pq

a1ao

-

<

0-

0.

o D CD

00

N=

CD

0wC

0 >

0-

0

a

After

the

12-month

follow-up,

the

study

population

was

reduced

to

a

pre-specified

cohort

(Safety

Population),

which

consists

of

all

subjects who received

a

study

stent

(ION

Stent

or

TAXUS

Express

Stent).

The

study

is

now

considered complete

with

regard

to

the

12-month

primary

endpoint.

The key

timepoints

are

shown

below

in

the

tables

summarizing

safety

and

effectiveness.

3.

Clinical

Endpoints

The

primary

endpoint

is

the rate

of

target

lesion

failure (TLF;

including

any

ischemia-driven

revascularization

of

the

target

lesion

[TLR],

myocardial

infarction

[MI;

Q-wave and

non-Q-wave]

the target

vessel,

or

cardiac

death

the

target

vessel)

at

12

months post-index procedure, testing non-inferiority

of

the

ION

Stent relative to

the

TAXUS

Express

Paclitaxel-Eluting

Stent control.

In-

segment percent

diameter

stenosis

at

9

months

post-index procedure

as

measured

by

quantitative

coronary

angiography

(QCA)

is

the

secondary

endpoint.

Both

the

primary

and

secondary

endpoints

were

analyzed

under

a

Bayesian

framework.

Bayesian analyses

can be

interpreted

in

a

more intuitive

way

than

conventional

frequentist

analyses

through

the

posterior

distributions

they

produce.

These

posterior

distributions

give

the

probability

that

a

parameter

of

interest

(e.g.

the

difference

in

the

rate

of

TLF

across

treatment

groups)

lies

within

a

certain

range,

given the

data

observed.

Therefore,

Bayesian

methods

can

provide

a

posterior

probability

that

the

non-inferiority

hypothesis

is

true

given

the

data

observed,

whereas

the

frequentist

P

value

provides

the

probability

of

observing

data

as

or

more

extreme

than

that

observed

assuming

the

non-inferiority

hypothesis

is

false.

Al.

Accountability

of

PMA

Cohort

At

the

time

of

database lock,

of

1262

subjects enrolled

in

PMA

study,

97.86%

(1235)

subjects

are

available

for

analysis

at

the

completion

of

the

study,

the

12-

month

primary

endpoint.

Subject

Disposition

for

PERSEUS

WH

Study,

ITT,

All

Subjects

(N=

262)

TAXUS

ION

Total

Express

(N=942)

(N=1262)

(N=320)

All Subjects

Treated

-

1264

Treated,

Not

Randomized

-

2 a

Intent-to-Treat

(ITT)

Analysis

Set

320

942

1262

Death

<395

days

with

no

12-month

Clinical

Follow-

2

6

8

up

Performed

Eligible

for

12-month

Clinical

Follow-up

318

936

1254

12-month

Clinical

Follow-Up

Visit

Performed

97.8%

97.6%

97.7%

(311/318)

(914/936)

(1225/1254)

Office

Visit

41

136

177

Telephone

Contact

270

776

1046

No

12-month

Clinical Follow-up

Visit

Performed

7

22

29

Premature

Discontinuation

3

9

12

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

27

4*

Subject

Disposition

for

PERSEUS

WH

Study,

ITT,

All

Subjects

(N=1262)

TAXUS

ION

Total

Express

(N=942)

(N=1262)

(N=320)

Withdrew

Consent

0

4 4

Lost

to

Follow-up

1 2

3

Other

2 3

5 d

Death

>395

days

0

0 0

Missed

12-month

Follow-up

Visit

4

13

17

With

Later

Follow-up

Visit

Performed

1 3 4

No

Later

Follow-up

Visit

Performed

3

10

13

12-month

Clinical Follow-Up

or

Death'

97.8%

97.7%

(313/320)

(920/942)

(1233/1262)

12-month

Clinical

Follow-Up

Subject

Accountability

97.2%

97.0%

97.1%

(311/320)

(914/942)

(1225/1262)

Numbers

are

%

(Count/Sample

Size)

or

Count.

a

Two

subjects

were

treated

without

randomization

and

therefore

are

not

included

in

the

analysis.

b

Subjects

who

died

prior

to

completion

of

follow-up

window

and

prior

to

completing

a

12-month

clinical

follow-up visit

are

considered

censored

and

are

excluded

from

calculation

of

proportion

of

subjects

who

completed

clinical

follow-up

visit.

c

Based

on

subjects

eligible

for

12-month

clinical

follow-up (excludes

deaths

within

395

days).

d

Four

subjects

withdrawn

at

the

investigator's

discretion

and

one

coded

as

a

"discontinuation"

(all

for

lack

of

follow-up)

Includes

subjects

who

have

died

in

both

the

numerator

and

the

denominator;

based

on

intent-to-treat

analysis

set.

f

Based

on

intent-to-treat

analysis

set.

Abbreviations:

ITT:

intent-to-treat;

TLF:

target

lesion

failure.

A2.

Study

Population

Demographics

and

Baseline

Parameters

Subjects

were

well-matched

for

baseline

demographics.

Age

was

slightly

lower

in

the

IONTM

Stent group

compared

to

the

TAXUS

Express

Stent control

(62±9.6

versus

63±9.5).

Baseline

lesion

characteristics:

Reference

vessel

diameter

was

2.78±0.48mm

and

2.75+0.47mm

in

the

ION

Stent

and

TAXUS

Express

Stent groups,

respectively,

with

baseline

lesion

length

of

14.2±6.1mm

and

14.1±5.8mm,

respectively.

Baseline

Demographic

and

Clinical

Characteristics,

ITT,

All

Subjects,

PERSEUS

WH

(N=1262)

TAXUS

Express

ION

(N=320) (N=942)

Male

68.8%

(220/320)

70.8%

(667/942)

Age

(yr)

63.5±9.5

(320)

62.2±9.6

(942)

(41.0,

82.0)

(33.0,

84.0)

Ethnicity

and

Race

Hispanic

or

Latino

1.9%

(6/320)

1.1%

(10/942)

Caucasian

92.5%

(296/320)

92.6%

(872/942)

Asian

1.9%

(6/320)

1.6%

(15/942)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

28

Baseline

Demographic

and

Clinical

Characteristics,

ITT,

All

Subjects,

PERSEUS

WH

(N=1262)

Parameter

TAXUS

Express

ION

(N=320) (N=942)

Black,

of

African

heritage

4.1%

(13/320)

3.9%

(37/942)

Native

Hawaiian

or other

Pacific

Islander

0.3%

(1/320)

0.4%

(4/942)

American

Indian

or

0.0%

(0/320)

0.3%

(3/942)

Alaska

native

Other

0.0%

(0/320) 0.4%

(4/942)

Cardiac

History

25.2% (80/318) 23.0%

(216/941)

6.3%

(20/319)

4.5%

(42/942)

19.0%

(60/316) 20.9%

(195/935)

CHF

7.5%

(24/318)

6.0%

(56/937)

Stable

Angina

66.6%

(213/320)

66.8% (629/941)

Unstable

Angina

21.3%

(68/320)

20.7%

(195/941)

Silent

Ischemia

12.2%

(39/320)

12.4%

(117/941)

Ejection

Fraction

(%)

57.8±9.8

(317)

58.0±9.3

(939)

(30.0,

98.0)

(30.0,

93.0)

Cardiac

Risk

Factors

Smoking,

Ever

69.5%

(216/311)

66.7%

(611/916)

Current

23.5% (73/311)

24.3%

(223/916)

(143/311)

42.4%

(388/916)

Medically

Treated

Diabetes

25.0%

(80/320)

24.6%

(232/942)

Insulin

Requiring

7.5%

(24/320)

7.3%

(69/942)

Non-insulin

Requiring

17.5%

(56/320)

17.3%

(163/942)

Hyperlipidemia

Req.

76.4%

(243/318)

76.3%

(717/940)

Medication

Hypertension

Req.

Medication

80.3%

(256/319)

75.3%

(709/941)

Family

History

of

CAD

66.4%

(196/295)

67.0%

(589/879)

Comorbidities

History

of

PVD

11.3%

(36/319)

10.6%

(99/938)

History

of

TIA

or

CVA

7.5%

(24/320)

5.7%

(54/941)

History

of

TIA

4.4%

(14/319)

3.2%

(30/940)

History

of

CVA

3.8%

(12/318)

3.2%

(30/940)

Renal

Disease

3.4% (11/320)

4.8%

(45/940)

History

of

GI

Bleeding

2.2% (7/319)

1.0%

(9/939)

Numbers

are

%

(Count/Sample

Size)

or

Mean±SD

(N)

(Min, Max).

Abbreviations:

CABG:

coronary

artery

bypass

graft;

CAD:

coronary

artery

disease;

CHF:

congestive

heart failure;

CI:

confidence

interval;

CVA:

cerebrovascular

accident;

GI:

gastrointestinal;

MI:

myocardial

infarction;

PCI:

percutaneous

coronary

intervention;

PVD:

peripheral

vascular

disease;

TIA:

transient

ischemic

attack.

Baseline

Lesion

Characteristics

by

QCA,

ITT,

All

Subjects,

PERSEUS

WH

(N=1262)

Lesion

Characteristic

TAXUS

Express

ION

(N=320)

(N=942)

Target Lesion

Vessel

LAD

43.8%

(140/320)

43.1%

(406/942)

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

29

LCX

21.6%

(69/320)

23.0%

(217/942)

RCA

34.7%

(111/320)

33.9%

(319/942)

Lesion

Location

Ostial

2.5%

(8/320)

2.7%

(25/942)

Proximal 40.0%

(128/320)

39.1%

(368/942)

Mid

48.1%

(154/320)

51.5%

(485/942)

Distal

9.4%

(30/320)

6.8%

(64/942)

Reference

Vessel

2.8±0.5

(320)

2.8±0.5

(942)

Diameter

(RVD,

mm)

(1.6,

4.6)

(1.4,

4.5)

Minimum

Lumen

0.8±0.4

(320)

0.8±0.3

(942)

Diameter

(MLD,mm)

(0.0,

2.1)

(0.0, 2.4)

Percent Diameter

Stenosis

71.7±10.9

(320)

72.1±10.9

(942)

(%

DS)

(40.0,

100.0)

(40.3,

100.0)

Lesion

Length

(mm)

14.1±5.8

(320)

14.2±6.1

(942)

(4.2,

40.9)

(3.2;

40.1)

Eccentric Lesion

50.3%

(161/320)

51.7%

(487/942)

Bend

(degrees)

>

45

6.9%

(22/320)

6.5%

(61/942)

>

90

0.3%

(1/320)

0.2%

(2/942)

Tortuosity,

Any

4.4%

(14/320)

6.3%

(59/942)

Moderate

4.1%

(13/320)

5.7%

(54/942)

Severe

0.3%

(1/320)

0.5%

(5/942)

Calcification,

Any

26.9%

(86/320) 24.2%

(228/942)

Moderate

22.2%

(71/320)

17.8%

(168/942)

Severe

4.7%

(15/320)

6.4%

(60/942)

Total

Occlusion

0.6%

(2/320)

0.6%

(6/942)

Bifurcation

40.3%

(129/320)

36.4%

(343/942)

25.7±28.8

(129)

24.4±28.1

(342)

(0.0,

95.0)

(0.0,

100.0)

Modified

ACC/AHA

A

8.8%

(28/320)

8.4%

(79/942)

BI

26.6% (85/320)

24.7%

(233/942)

B2

40.6%

(130/320)

40.8%

(384/942)

C

24.1%

(77/320)

26.1%

(246/942)

Pre-Procedure

TIMI

Flow

0

0.6%

(2/320)

0.2%

(2/942)

1

0.0%

(0/320)

0.4%

(4/942)

2

1.3%

(4/320)

3.6%

(34/942)

3

98.1%

(314/320)

95.8%

(902/942)

Numbers

are

%

(Count/Sample

Size)

or

Mean±SD

(N)

(Min,

Max).

Abbreviations:

ACC/AHA:

American

College

of

Cardiology/American

Heart

Association;

CI:

confidence

interval;

DS:

diameter

stenosis;

LAD:

left

LCX: left

circumflex;

MLD:

minimum

lumen

diameter;

QCA:

quantitative

coronary

angiography;

RCA:

right

coronary

artery; RVD:

reference

vessel

diameter;

TIMI:

thrombolysis

in

myocardial infarction.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

30

A3.

Safety

and

Effectiveness

Results

1.

Safety

Results

The

analysis

of

safety

was

based

on

the

ION

stent

cohort

of

942

subjects

available

for the 12-month

primary

endpoint

evaluation.

Principal adverse

events

for

this

study

are

presented

in

Table

13

below.

Table

13:

Principal

Adverse

Events

PERSEUS

Workhorse

to

1

Year

TAXUS

ION

Stent Express

(N=942)

Stenta

(N=320)

In-Hospital

MACE

1.9%

(18/942)

2.5%

(8/320)

30-Day

MACE

2.2%

(21/939)

3.1%

(10/319)

9-Month

MACE

5.6%

(52/932)

6.3%

(20/317)

Cardiac

Death

0.3%

(3/932)

0.3%

(1/317)

MI

2.0%

(19/932)

2.8%

(9/317)

Q-Wave

MI

0.4%

(4/932)

0.0%

(0/317)

Non-Q-Wave

MI

1.6%

(15/932)

2.8%

(9/317)

TVR

4.0%

(37/932)

4.4%

(14/317)

TLR

2.6%

(24/932)

3.5%

(11/317)

Non-TLR

1.9%

(18/932)

1.3%

(4/317)

1-Year

MACE 7.4%

(68/922)

7.7%

(24/313)

Cardiac Death

0.5%

(5/922)

0.3%

(1/313)

MI

2.2%

(20/922)

2.9%

(9/313)

Q-Wave

MI

0.5%

(5/922)

0.0%

(0/313)

Non-Q-Wave

MI

1.6%

(15/922)

2.9% (9/313)

TVR

5.6%

(52/922)

5.8%

(18/313)

TLR

3.8%

(35/922)

4.5% (14/313)

Non-TLR

2.5%

(23/922)

1.96/(6/313)

1-Year

ARC

Stent

Thrombosis

Definite

or

Probable

0.4%

(4/918)

0.3%

(1/313)

Definite

0.3%

(3/918)

0.3%

(1/313)

Probable

0.1%

(1/918)

0.0% (0/313)

'DES

Control

An

angiographic

core

laboratory

review

of

all

available

angiograms

in

the

PERSEUS

Clinical

Trial

revealed

a

total

of

3

stent fractures

-

2

ION

stent fractures

(Type

33

fractures

that

were

seen

on angiograms

performed

at 286

and

259

days

post-stent

implantation)

and

1

Taxus Express

stent

fracture

(Type

43

fracture

noted

on

an

angiogram

performed

861

days

post-stent

implantation).

Only

the fracture

that

occurred

with

the

Taxus

Express stent

was

associated

with

a

major

adverse

cardiovascular

event

(a

TLR).

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

31

2.

Effectiveness

Results

The

analysis

of

effectiveness

was

based

on the

942

subjects

available

for

the

12-

month

primary

endpoint

evaluation.

Key

safety

and

effectiveness

outcomes

are

presented

in Tables

14

through

19.

Table

14:

PERSEUS

Workhorse

Clinical

Results

1-year

(ITT

population)

ION

Stent

TAXUS

Express

Stent'

(N=942)

(N=320)

EFFICACY

TVR,

Overall

5.6%

(52/922)

5.8%

(18/313)

TLR,

Overall

3.8%

(35/922)

4.5%

(14/313)

TLR,

PCI

3.6%

(33/922)

4.2%

(13/313)

TLR,

CABG

0.3%

(3/922)

0.6%

(2/313)

Non-TLR,

Overall

2.5%

(23/922)

1.9%

(6/313)

Non-TLR,

PCI

2.3%

(21/922)

1.6%

(5/313)

Non-TLR,

CABG

0.3%

(3/922)

1.0%

(3/313)

SAFETY

Total

Death

0.7%

(6/922)

0.6%

(2/314)

Cardiac

Death

or MI

2.5%

(23/922)

2.9%

(9/313)

Cardiac

Death

0.5%

(5/922)

0.3%

(1/313)

MI

2.2%

(20/922)

2.9%

(9/313)

Q-wave

MI

0.5%

(5/922)

0.0% (0/313)

Non-Q-Wave

MI

1.6%

(15/922)

2.9%

(9/313)

ARC

Stent Thrombosis

Definite

or

Probable

0.4%

(4/918)

0.3%

(1/313)

Definite

0.3%

(3/918)

0.3%

(1/313)

Probable

0.1%

(1/918)

0.0% (0/313)

a

DES

Control

b

Timing

of

non-Q-wave

Ml:

15/15 ION

events

and

8/9

TAXUS

Express events

occurred

peri-procedurally.

This

trial

was

not sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Abbreviations:

ARC=Academic

Research

Consortium;

CABG=coronary

artery

bypass

graft;

DES=drug-eluting

stent;

MI=myocardial

infarction;

PCI=percutaneous

coronary

intervention;

TLR=target

lesion

revascularization;

TVR=target

vessel

revascularization.

Primary

Endpoint

(12-Month

TLF):

The

primary

endpoint

was

met:

There

is

a

99.96%

Bayesian

posterior

probability

that

ION

Stent

is

non-inferior

to

TAXUS

Express

Stent (given

the

data observed),

demonstrating non-inferiority

of

the

ION

Stent

versus

the

TAXUS

Express

Stent.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness Data

Page

32

Table

15:

PERSEUS

Workhorse

Primary

Endpoint

TAXUS

Express

12-Month

ION

Stent

Difference

Posterior

Target

Lesion

Posterior Posterior

Posterior

b

Probabilit

95%

C

Failure

(TLF)

Mean

(SD)

Mean

(SD)

Mean

(SD)

A

y

of

NI

c

Per

Protocola

5.568%

6.38%

-0.570%

1.85%

4.1%

0.9996

(0.0076)

(0.0136)

(0.0155)

a

Primary

analysis for

assessing hypothesis

of

non-inferiority

and

study

success criterion.

For

per

protocol analyses, only

ITT

PERSEUS

Workhorse

trial

subjects

who

had

the

randomly

assigned

study

stent implanted

in

the

target

coronary

artery were included.

b

1-Sided

950Z

posterior

credible

interval,

based

off

the

95th

percentile

of

the

posterior

distribution.

Posterior probability

that

the

difference

in

the

rate

of

12-month

TLF between

ION

Stent and

TAXUS

Express

Stent

is

less

than

the

pre-specified

margin

of

4.1%,

given the data.

12-Month

TLF:

the

proportion

of

subjects

who

experience

a

TLF

up

to

365

days

post-procedure

out

of

the

population

that

have been

followed

for

at least

335

days or who

have

experienced

a

TLF

up

to

335

days

post-procedure.

Secondary

Endpoint

(9-Month

%DS):

The

secondary

endpoint

was

met:

There

is

a

99.70%

Bayesian posterior

probability

that

IONTM

Stent

is

non-inferior

to

TAXUS

Express

Stent (given

the data observed),

demonstrating

non-inferiority

of

the

ION

Stent versus

the

TAXUS

Express Stent.

Table

16:

PERSEUS

Workhorse

Secondary

Endpoint

TAXUS

Ln

(9-

Express

Month

In-

Stent

ION

Stent

Difference

Posterior

Segment

Posterior Posterior

Posterior

95%

CIb

Probabilit

%DS)

Mean

(SD)

Mean

(SD)

Mean

(SD)

A

y

of

NI

C

Per

3.117

3.087

-0.0294

01078

0.20

0.9970

Protocola

(0.0736)

(0.0374)

(0.08253)

1

a

Primary

analysis

for

assessing

hypothesis

of

non-inferiority.

For

per

protocol

analyses,

only

ITT

PERSEUS

Workhorse

trial

subjects who

had

the

randomly assigned

study stent implanted

in

the

target

coronary artery

were included.

b

1-Sided

95%

posterior

credible

interval,

based

off

the

95th

percentile

of

the

posterior

distribution.

Posterior

probability

that

the

difference

in

mean

In

(9-month

%DS)

between

ION

Stent

and

TAXUS

Express

Stent

is

less

than

the

pre-specified

margin

of

0.20, given

the

data.

The

secondary

endpoint

is

9-month

in-segment

%DS.

For

the

secondary

endpoint,

a

natural

log

(In)

transformation

was

used

to

improve

the

normality

of

the

distribution.

Analyses

are

performed

on

the

transformed

data.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

33

Table

17:

PERSEUS

Workhorse

Angiographic

Results

TAXUS

Express

ION

Stent

Stentb

Angiographic

Outcomes

a(N=228)

(N=61)

MLD

(mm),

In-stent

Post-Procedure

2.68±0.39

(228)

2.54±0.36

(61)

9-Month

2.34±0.67

(228)

2.28±0.64

(61)

MLD

(mm),

Analysis

Segment

Post-Procedure

2.25±0.49

(228)

2.16±0.37

(61)

9-Month

2.08±0.63

(228)

2.00±0.56

(61)

Acute

Gain

(mm),

In-stent

1.93±0.41

(228)

1.83±0.40

(61)

Acute

Gain,

Analysis

Segment

1.51±0.48

(228)

1.45±0.40

(61)

(mm)

%

DS,

In-stent

Post-Procedure

4.10±10.13

(228)

5.64±8.05

(61)

9-Month

16.37±20.86

(228)

16.02±20.61

(61)

%

DS,

Analysis

Segment

Post-Procedure

20.21±9.71

(228)

19.87±7.57

(61)

9-Month

26.10±17.71

(228)

26.37±17.47

(61)

Late Loss,

In-stent

(mm)

0.34±0.55

(228)

0.26±0.52

(61)

Late Loss,

Analysis

Segment

(mm)

0.17±0.48

(228)

0.16±0.45

(61)

Binary

Restenosis

In-stent

restenosis

7.9%

(18/228)

6.6%

(4/61)

Analysis

segment

restenosis

8.8%

(20/228)

9.8%

(6/61)

a

Includes

all

subjects

in

the

angiographic

subset

with

paired lesion

data.

b

DES

Control

Abbreviations:

DES=drug-eluting

stent;

DS=diameter

stenosis;

MLD=minumum

lumen

diameter.

Table

18:

PERSEUS

Workhorse

Stent

Thrombosis

ION

Stent

TAXUS

Express

Stentc

(N=942)

Set

Intent-to-Treat

Population

(N=320)

Protocol

Defined

Stent

Thrombosis

a

Cumulative

through

1

year

0.4%

(4/918)

0.3%

(1/313)

Acute

ST

0.2%(2/942)

0.3%

(1/320)

(524

hrs)

Subacute

ST

0.0%

(0/939)

0.0%

(0/319)

(>24

hrs

and

!30

days)

Late

ST

(>30

ays

nd

2

moths)0.2%

(2/936)

0.0%

(0/3

17)

(>30

days

and:512

months)

i

ARC

Definite

&

Probable

Stent

Thrombosis

b

Cumulative

through

1

year

0.4%

(4/918)

0.3% (1/313)

Acute

ST

0.2%

(2/942)

0.3%

(1/320)

(S24

hrs)

Subacute

ST

(>24hrs

nd

30

dys)0.0%

(0/939)

0.0%

(0/3

19)

(>24

hrs

and:530

days)

Late

ST

(>30

ays

nd

<2

moths)0.2%

(2/936)

0.0%

(0/3

17)

(>30 days

and:512

months)

To

be

included

in

the

calculation

of

stent

thrombosis

(ST)

rate

for

a

given

interval,

a

patient

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

34

either

had

to have

a

stent

thrombosis

during

the

interval

(e.g.

31-365

days

inclusive)

or they

had

to

be

stent

thrombosis-free

during

the

interval

with

last

follow-up

on

or

after

the

first

day

of

the given interval (e.g.

31

days).

a

Per

protocol,

stent

thrombosis

is

defined

as

the

occurrence

of

any

of

the

following:

1.

Clinical

presentation

of

acute

coronary syndrome

with

angiographic

evidence

of

stent

thrombosis:

a)Angiographic

documentation

of

a

complete occlusion

(TIMI

flow

0

or

1)

of

a

previously

successfully treated

artery (TIMI

flow

2

to

3

immediately

after stent placement

and

diameter

stenosis

530%)

and/or

b)

Angiographic

documentation

of

a

flow-limiting thrombus

within

or

adjacent

to

a

previously

successfully

treated

lesion.

2.

Acute

MI

of

the

distribution

of

the

treated

vessel.

3.

Death within

the first

30

days

(without

other

obvious

cause)

is

considered

a

surrogate

for

stent

thrombosis

when

angiography

is

not available.

b

Academic

Research

Consortium

(ARC)

stent

thrombosis

is

defined

as

follows

4

:

1.

Definite

ST

is

considered

to

have

occurred

after

intracoronary

stenting

by

either angiographic

or

pathologic

confirmation

of

stent

thrombosis.

2.

Probable

ST

is

considered

to have

occurred

after intracoronary

stenting

in

the

following

cases:

a)

Any

unexplained

death

within

the

first

30

days

following

stent

implantation.

b)

Irrespective

of

the

time after

the index

procedure,

any

MI

which

is

documented

acute

ischemia

in

the

territory

of

the

implanted stent

without angiographic

confirmation

of

ST

and

in

the

absence

of

any

other obvious

cause.

DES

Control

Numbers

are

%

(Count/Sample

Size).

This

trial

was

not sized to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Figure

3:

PERSEUS

Workhorse

Cumulative

Rate of

Target

Lesion

Failure

to

12

Months,

Intent-to-Treat,

Event Rate

±

1.5

SE,

All

Subjects

(N=1262)

20

-

woo

TAXUS

Express

Stent

(N=320)

ION

Stent

(N=942)

g 15

N

10

6.0%

0

30

60

90 120

150

180

210 240

270 300 330

360

390

Days

Since

Index

Procedure

TAXUS

Express

Stent:

320

311

310

309 308

307 306 305

301

ION

Stent:

942

921

918 914 913 910

905

900

887

Event Rate Event

Free

ION

Stent

5.6%

94.4%

TAXUS

Express

Stent

DES

6.0%

94.0%

Control

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data Page

35

/

Figure

4:

PERSEUS

Workhorse

Cumulative

Frequency

Distribution

of

9-Month

In-

Segment

Percent

Diameter

Stenosis

by

QCA,

Intent-to-Treat,

All

Angiographic

Subset

Patients

(N=330)

100

-

80 -

m

ION

,A E I TAXULS

Stenit

Express

Stent

60

- ,

(N=228) (N=61)

- ----

- - ---

- -- -

- - --- -- -

- - - Median

20.57

20.81

a)

Minimum

3.31

7.56

40

-

Maximum

100

Mean

26.1

26.37

20

-

I

Standard

Deviation

17.71

17.47

Coefficient

of Var. 67.84% 66.25%

0*

0

20

40

60

80

100

Observed

Value

Results

in

subjects

with and

without

diabetes: Subjects

with diabetes

mellitus

represent

a

high-risk

group

for

adverse

events

following percutaneous

coronary

intervention. Table

19

shows

1-year

outcomes

in

subjects

with

and

without

medically

treated

diabetes (defined

as

treatment

with

oral

hypoglycemic agents

or

insulin

at

enrollment).

While

the

PERSEUS

WH

study

randomization

was

stratified

for

diabetic

status,

this trial

was

not

adequately

powered

to

study

safety

or

effectiveness

of

the

TAXUS

Express

Stent

versus

the

ION

Stent

in

subjects

with

or

without

diabetes

and was

not

designed

to

specifically support

an

approval

for use

in

diabetic subjects.

These

exploratory

analyses

suggest that

in

subjects

treated

with

the

ION

Stent,

1-year

TLR

rates

were

4.9%

in

diabetic

and

3.4%

in

non-diabetic

subjects.

Table

19:

PERSEUS

Workhorse

Clinical

Results

in

Subjects with

and

without

Medically

Treated

Diabetes

I-year

(ITT

Population)

ION

Stent

Subjects

With

ION

Stent

Subjects

Medically

Treated

Without

Medically

Treated

Diabetes

(N=232)

(N=710)

EFFICACY

TVR,

Overall

7.6%

(17/223)

5.0%

(35/699)

TLR,

Overall

4.9%

(11/223)

3.4%

(24/699)

TLR,

PCI

4.5%

(10/223)

3.3%

(23/699)

TLR,

0.4%

(1/223)

0.3%

(2/699)

CABG

Non-TLR,

3.6%

(8/223)

2.1%

(15/699)

Overall

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

36

Table

19:

PERSEUS

Workhorse

Clinical

Results

in

Subjects

with

and without

Medically

Treated

Diabetes

I-year

(ITT

Population)

ION

Stent

Subjects

With

ION

Stent

Subjects

Medically

Treated

Without

Medically

Treated

Diabetes

(N=-232)

(N=7

10)

Non-TLR,

2.7%

(6/223)

2.1%

(15/699)

PCI

Non-TLR,

0.9%

(2/223)

0.1%

(1/699)

CABG

SAFETY

Total

Death

1.4%

(3/222)

0.4% (3/700)

Cardiac

Death

or

MI

3.1%

(7/223)

2.3%

(16/699)

Cardiac

Death

1.3%

(3/223)

0.3%

(2/699)

MI

2.2%

(5/223)

2.1%

(15/699)

MI

Q-wave

0.9%

(2/223)

0.4%

(3/699)

Non-Q-

1.3%

(3/223)

1.7%

(12/699)

wave

MI

ARC

Stent

Thrombosis

Definite

or

Probable

0.5%

(1/220)

0.4% (3/698)

Definite

0.0%

(0/220)

0.4% (3/698)

Probable

0.5%

(1/220)

0.0%

(0/698)

This

trial was not

sized

to

determine

the

rate

of

low

frequency

events with

a

pre-specified

precision.

Abbreviations:

ARC=Academic

Research

Consortium;

CABG=coronary

artery

bypass

graft;

DES=drug-eluting

stent;

MI~myocardial

infarction;

PCI=percutaneous

coronary

intervention;

TLR-target

lesion

revascularization;

TVR=target

vessel

revascularization.

B.

PERSEUS

SV

Clinical

Trial

Primary

Objective:

The

primary

objective

of

the

PERSEUS

SV

study

was

to

evaluate

the

safety

and

efficacy

of

the

ION

TM

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System

for the

treatment

of

de

novo

atherosclerotic

lesions

of

<20mm

in

length

in

native

coronary

arteries

with

visual

RVD

of

>2.25mm

to

<2.75mm

diameter.

Design:

PERSEUS

Small

Vessel

is

a

prospective,

single-arm,

open-label

superiority

trial

that compares

the

ION

Stent

to

a

matched

bare

metal

(Express

Stent)

historical

control

group

comprised

of

subjects

with

reference

vessel

diameter

(RVD)

>2.25mm

to

<2.75mm

and

lesion

length

<20mm

garnered

from

the

TAXUS

V

trial.

Eligible

subjects

were

those

>18

years

old

with

documented

stable

angina

pectoris,

unstable angina

pectoris,

or

documented

silent

ischemia

and

left

ventricular

ejection

fraction

(LVEF)

>30%.

De

novo

target

lesions

in

a

native

coronary

artery

with

diameter

stenosis

>50%,

reference

vessel

diameter

>2.25mm

to

<2.75mm,

and

cumulative

lesion

length

520mm

coverable

by

a

single

study

stent

were

eligible.

Multiple

stenting was

allowed

for

bail-

out

only.

The

protocol

mandated

antiqlatelet

therapy

compliance

in

accordance

with

the

ACC/AHA/SCAI

Guidelines

for

PCI.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

37

Enrollment

of

224

subjects

was

planned.

A

total

of

224

subjects

were

enrolled

at

28

centers.

Of

the

224

subjects

included

in

the

intent-to-treat analysis

set, a

total

of

197

subjects

were

evaluable

for the

9-month

primary

endpoint

of

in-stent

late

loss.

The

control

group

consisted

of

125

matched

bare metal

Express

subjects

from

the

TAXUS

V

trial,

including

108

with 9-month

QCA

follow-up.

An

angiographic

core

lab

was

utilized

for

analysis

of

angiography

data.

A

Clinical

Events

Committee

(CEC)

served

as

a

multidisciplinary

expert

group

responsible

for

the

independent

and

ongoing adjudication

of

prespecified

clinical events,

including

all

reported deaths, myocardial

infarctions

(MI),

target

vessel

revascularizations

(TVR),

and

stent

thromboses

(ST),

as

defined

by

the

clinical

protocol.

A

Data

Monitoring

Committee

(DMC)

of

independent

experts

in

cardiology,

cardiovascular

interventional

therapy,

and

biostatistics

worked

to

ensure

patient

safety

by

evaluating

accumulating

data

from

the

PERSEUS

Clinical

Program.

1.

Clinical

Inclusion

and

Exclusion

Criteria

The

clinical

inclusion

and

exclusion

criterion

are

identical

to

those

described

in

Section

IX.A.

1.

with

the

following

exception:

ANGIOGRAPHIC

INCLUSION

(by

visual

estimate)

*

Reference

vessel

diameter

(RVD):

>2.25mm

to

<2.75mm

*

Cumulative

target lesion length

(area

to

be

treated

must

be

completely

coverable

by

one

study

stent):

<20mm

2.

Follow-up

Schedule

Follow-up

included

clinical

assessments

at

30

days,

9,

12

and

18

months,

and

2,

3,

4

and

5

years

post

index

procedure.

The

same

examination

schedule

as

outlined

in

Table

12,

above,

was utilized

for the

PERSEUS

SV

trial,

with

one

exception.

All

224

enrolled

subjects

were

required

to

undergo

protocol-

mandated

9-month

angiographic

follow-up.

Angiographic

assessments

were

performed

for

the

area

of

the

vessel

within

the

stent

margins

(in-stent)

and

the

areas

immediately

5

mm

proximal

and

distal

from

the

stent

margins

(analysis

segment).

After

the 12-month

follow-up,

the

study

population

was reduced

to

a pre-

specified

cohort

(Safety

Population),

which

consists

of

all

subjects

who

received

a

study

stent

(ION

Stent).

The

study

is

now considered

complete

with

regard

to

the

9-month

primary

and

12-month

secondary

endpoints.

3.

Clinical

Endpoints

The

primary

endpoint

is

in-stent

late

loss

by

QCA

on

9-month

follow-up

(ION

Stent

compared

to

bare

metal

Express

Stent)

and

the

secondary

endpoint

is

target

lesion

failure

(TLF;

including

any

ischemia-driven

revascularization

of

the

target

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

38

lesion

[TLR],

myocardial infarction

[MI;

Q-wave

and

non-Q-wave]

the

target vessel,

or

cardiac death related

to

the

target

vessel)

at

12

months

(ION

Stent

compared

to

a

performance

goal

based

on

TAXUS

Express

Stent

results

from

the

TAXUS IV

and

TAXUS

V

trials).

(The

TAXUS

Express

Stent

is

an

earlier

generation stent with

the same

drug/polymer

coating

formulation

as

the

ION

Stent

System.)

The

study

success criteria

are

met

when both

the

primary

and

secondary

endpoints

are

met, that

is,

when

mean

in-stent

late

loss

at

9

months post-index

procedure

for

the

ION

Stent

group

is

shown

to

be

superior

to

that

of

the

historical

control

and

the

12-month

TLF

rate

for the

ION

Stent

group

is

shown

to

be

less

than

the

19.5%

performance

goal,

which

is

based

on

TAXUS

Express

Stent

results

in

lesion-matched

subjects

in

TAXUS

IV

and

TAXUS

V.

B1.

Accountability

of

PMA

Cohort

At

the

time

of

database lock,

of

224

subjects

enrolled

in

PMA

study,

87.94%

(197)

subjects

are

available

for

analysis

at

the

completion

of

the

study,

for the

9-

month primary

endpoint.

Subject

Disposition

for

PERSEUS

SV,

ITT,

All

Subjects

(N=349)

Historical

ION

Total

Control

BMS

(N=224)

(N=349)

(N=125)

Intent-to-treat

analysis

set

a

125

224

349

Death

5395

days

with

no

12-month

Clinical

2

3

5

Follow-up Performed

Eligible

for

12-month

Clinical

Follow-upb

123

221

344

97.6%

97.3%

97.4%

12-month

Clinical

Follow-Up Visit

Performede

(2/2)25/13534

(120/123)

(215/

221)

(335/344)

Office

Visit

10

28

38

Telephone

Contact

110

187

297

No

12-month

Clinical

Follow-up

Visit

Performed

3 6 9

Premature

Discontinuation

3 4 7

Withdrew

Consent

3

2 5

Lost

to

Follow-up

0 2

2

Other

0 0

0

Death

>395

days

0 0

0

Missed

12-month

Follow-up Visit

0 2 2

With

Later

Follow-up

Visit

Performed

0 0

0

No Later

Follow-up

Visit

Performed

0 2

2

d

97.6%

97.3%

97.4%

12-month

Clinical

Follow-Up

or

Deathd(2/5)2124)3049

(122/125)

(218/224)

(340/349)

12-month

Clinical

Follow-Up

Subject

96.0%

Accountabilitye

(120/125)

(215/224)

(335/349)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

39

Numbers

are

%

(Count/Sample

Size)

or

Count.

a.

Intent-to-treat

is

the

primary

analysis

set

for

the

testing

of

the

primary

endpoint,

in-stent

late

loss

at

9

months,

and the

secondary

endpoint,

12-month

TLF.

For

intent-to-treat

analyses,

all

TAXUS

PERSEUS

Small

Vessel

subjects

who

signed

the

IRB/EC-approved

written

Informed

Consent

Form

and

are

enrolled

in

the

study are

included

in

the

analysis,

regardless

of

whether

or

not

the

TAXUS

Element

Stent

was

implanted.

b.

Subjects

who

died

prior

to

completion

of

follow-up

window

and

prior

to

completing

a

12-month

clinical

follow-up

visit

are

considered

censored

and

are

excluded

from

calculation

of

proportion

of

subjects

who

completed

clinical

follow-up

visit.

c.

Based

on

subjects

eligible

for

12-month

clinical

follow-up

(excludes deaths

within

395

days).

d.

Includes subjects

who

have

died

in

both

the

numerator

and

the

denominator;

based

on

intent-to-treat

analysis

set.

e.

Based

on

intent-to-treat analysis

set.

Abbreviations:

BMS:

bare

metal

stent

(Express);

ITT:

intent-to-treat;

TLF:

target

lesion

failure.

B2.

Study

Population

Demographics

and

Baseline

Parameters

Demographics:

The

IONTM

Stent

group had

a

higher

rate

of

prior congestive

heart

failure

(8.1%

versus 2.4%),

previous smoking (48.6%

versus

36.8%),

and

higher

baseline

ejection

fraction

(57.9±9.4

versus 55.0±9.2)

as

compared with

the

historical BMS

control group.

The

ION

Stent

group had

lower

rates

of

baseline

unstable

angina

(20.1%

versus

29.6%)

and

current

smoking

(13.6%

versus

22.2%).

Baseline

lesion

characteristics:

Differences

in

the

ION

Stent

group

compared

to the

historical BMS

control

group

included shorter

lesion

length

(11.7±5.1

versus

12.9±5.1),

lower

incidence

of

ACC/AHA

Type B2/C

lesions

(58.0%

versus

77.6%),

and

lower

incidence

of

tortuosity

(8.9%

versus

18.4%).

However,

baseline

RVD

and

MLD

were significantly lower

in

ION

Stent

subjects

than

in

the

BMS

historical

control

(2.08±0.28 versus 2.19±0.35

for

RVD

and

0.55±0.23 versus

0.62±0.24

for

MLD,

respectively).

These

differences

were

not

expected

to

affect

outcomes variables,

as

propensity

score

adjustments showed

no change

in

the

outcome or conclusion

of

the

trial.

Baseline

Demographic

and Clinical

Characteristics,

ITT,

All

Subjects,

PERSEUS

SV

(N=349)

Historical Control

ION

BMS

(N=125)

(N=224)

Male

60.8% (76/125) 63.8%

(143/224)

64.2±10.9

(125)

64.7±10.3

(224)

Age(yr)

(41.0,

85.0)

(37.0,

85.0)

Ethnicity

and

Race

Hispanic

or

Latino

2.4%

(3/125)

4.9%

(11/224)

Caucasian

92.0%

(115/125)

91.1%

(204/224)

Asian

0.0%

(0/125)

0.0%

(0/224)

Black,

of

African heritage

4.0%

(5/125)

2.7%

(6/224)

Native

Hawaiian

or

other

NA

0.0%

(0/224)

Pacific Islander

American

Indian

or

0.0%

(0/125)

0.4%

(1/224)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness Data

Page

40

A

Baseline

Demographic

and

Clinical

Characteristics,

ITT,

All

Subjects,

PERSEUS

SV

(N=349)

Historical Control

ION

BMS

(N=125)

(N=224)

Alaska

native

Other

1.6%

(2/125)

0.9%

(2/224)

Cardiac History

33.9%

(42/124)

41.3%

(92/223)

19.5%

(24/123)

18.4%

(41/223)

29.0%

(36/124)

25.8%

(57/221)

CHF

2.4%

(3/124)

8.1%

(18/222)

Stable

Angina

56.0%

(70/125)

60.7% (136/224)

Unstable Angina

29.6%

(37/125)

20.1%

(45/224)

Silent Ischemia

15.3%

(18/118)

19.2%

(43/224)

Fraction

(%)

55.0±9.2

(123)

57.9±9.4

(223)

(25.0,

75.0)

(30.0,

84.0)

Cardiac

Risk

Factors

Smoking,

Ever

59.0%

(69/117)

62.3%

(137/220)

Current

22.2% (26/117)

13.6%

(30/220)

(43/117) 48.6%

(107/220)

Medically

Treated

32.0%

(40/125)

36.6%

(82/224)

Diabetes

Insulin

Requiring

12.0%

(15/125)

16.5%

(37/224)

Non-insulin

Requiring

20.0%

(25/125)

20.1%

(45/224)

Hyperlipidemnia

Req.

77.6%

(97/125)

85.7%

(191/223)

Medication

Hypertension

Req.

80.0%

(100/125)

80.8%

(181/224)

Medication

Family History

of

CAD

69.5%

(73/105) 67.6%

(144/213)

Comorbidities

History

of

PVD

12.0%

(14/117)

10.8%

(24/223)

History

of

TIA

or

CVA

4.0%

(5/124)

9.4% (21/223)

Renal

Disease

NA

4.1%

(9/222)

History

of

GI

Bleeding

1.6%

(2/125)

2.3%

(5/221)

Numbers

are

%

(Count/Sample

Size)

or

Mean+SD

(N)

(Min,

Max).

Abbreviations:

BMS:

bare

metal

stent

(Express);

CABG:

coronary

artery

bypass

graft;

CAD:

coronary

artery

disease;

CHF:

congestive

heart

failure;

Cl:

confidence

interval;

CVA:

cerebrovascular

accident;

GI:

gastrointestinal;

MI:

myocardial

infarction;

PCI:

percutaneous

coronary

intervention;

PVD:

peripheral

vascular

disease;

TIA:

transient

ischemic

attack.

Baseline Lesion

Characteristics

by

QCA,

ITT,

All

Subjects,

PERSEUS

SV

(N=349)

Historical

Control

ION

BMS

(N=125)

(N=224)

Target

Lesion Vessel

LAD

42.4%

(53/125)

37.9%

(85/224)

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

41

Baseline

Lesion

Characteristics

by

QCA,

ITT,

All

Subjects,

PERSEUS

SV

(N=349)

Historical

Control

ION

BMS

(N=125)

(N=224)

LCX

36.0%

(45/125)

41.5%

(93/224)

RCA

21.6% (27/125)

20.5%

(46/224)

Lesion

Location

Ostial

4.0%

(5/125)

6.3%

(14/224)

Proximal

33.6%

(42/125)

40.6%

(91/224)

Mid

44.8%

(56/125)

44.6%

(100/224)

Distal

17.6%

(22/125)

8.5%

(19/224)

Reference

Vessel

Diameter

2.2±0.4

(125)

2.1±0.3

(224)

(RVD,

mm)

(1.2,3.1)

(1.4,3.0)

Minimum

Lumen

Diameter

0.6±0.2

(125)

0.6±0.2

(224)

(MLD,

mm)

(0.2,

1.4)

(0.0,

1.2)

Percent

Diameter

Stenosis

71.5±10.4

(125)

73.5±10.2

(224)

(%

DS)

(40.5,

90.0)

(49.4,

100.0)

Lesion

Length

(mm)

12.9±5.1

(125)

11.7±5.1

(224)

(5.0,

25.7)

(3.8,

29.8)

Eccentric

Lesion

62.4%

(78/125)

66.5%

(149/224)

Bend

(degrees)

> 45

12.0%

(15/125)

6.3%

(14/224)

>90

0.0%

(0/125)

0.0%

(0/224)

Tortuosity,

Any

18.4%

(23/125)

8.9%

(20/224)

Moderate

13.6%

(17/125)

8.0%

(18/224)

Severe

4.8%

(6/125)

0.9%

(2/224)

Calcification,

Any

20.8% (26/125)

13.4%

(30/224)

Moderate

17.6%

(22/125) 9.4%

(21/224)

Severe

3.2%

(4/125)

4.0% (9/224)

Total Occlusion

0.8%

(1/125)

1.3%

(3/224)

Bifurcation

21.6%

(27/125)

23.7%

(53/224)

Sidebranch Stenosis

16.0±21.2

(27)

18.1±24.6

(53)

(0.0,

80.0)

(0.0,

90.0)

Modified

ACC/AHA

A

5.6%

(7/125)

9.4%

(21/224)

B

16.8%

(21/125)

32.6%

(73/224)

B2

58.4%

(73/125)

44.2%

(99/224)

C

19.2%

(24/125)

13.8%

(31/224)

Pre-Procedure

TIMI

Flow

0

0.0%

(0/125)

0.4%

(1/224)

1

0.8%

(1/125)

0.9%(2/224)

2

5.6%

(7/125)

0.4%

(1/224)

3

93.6%

(117/125)

98.2%

(220/224)

Numbers

are

%

(Count/Sample

Size)

or

Mean±SD

(N)

(Min, Max).

Abbreviations:

ACC/AHA:

American

College

of

Cardiology/American

Heart

Association;

BMS: bare

metal

stent

(Express);.CI:

confidence

interval;

DS:

diameter

stenosis;

LAD:

left

LCX: left

circumflex;

MLD:

minimum

lumen

diameter;

QCA:

quantitative

coronary

angiography;

RCA:

right coronary

artery;

RVD:

reference

vessel

diameter;

TIMI:

thrombolysis

in

myocardial infarction.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

42

B3.

Safety

and

Effectiveness

Results

1.

Safety

Results

The

analysis

of

safety was

based

on

the

ION

stent cohort

of

224

subjects

available

for

the

9-month primary

endpoint.

The

principal adverse

events

for

this

study

are

presented

below

in

Table

20.

Table

20:

Principal

Adverse

Events

PERSEUS

Small

Vessel

to

1

Year

Express

ION

Stent

Stentb

(N=224)

(N=125)

In-Hospital

MACE

0.0%

(0/224)

1.6%

(2/125)

30-Day

MACE 0.9%

(2/221)

2.4%

(3/124)

9-Month

MACE

7.8%

(17/218)

14.6%

(18/123)

Cardiac

Death

0.9%

(2/218)

0.8%

(1/123)

MI

0.9%

(2/218)

2.4%

(3/123)

Q-Wave

MI

0.5%

(1/218)

0.0%

(0/123)

Non-Q-Wave

MI

0.5%

(1/218)

2.4%

(3/123)

TVR

6.9%

(15/218)

12.2%

(15/123)

TLR

3.7%

(8/218)

10.6%

(13/123)

Non-TLR

5.0%

(11/218)

4.1%

(5/123)

1-Year

MACE

12.4%

(27/218)

27.3%

(33/121)

Cardiac

Death

1.4%

(3/218)

0.8%

(1/121)

MI

0.9%(2/218)

2.5%

(3/121)

Q-Wave

MI

0.5%

(1/218)

0.0%

(0/121)

Non-Q-Wave

MI

0.5%

(1/218)

2.5%

(3/121)

TVR

11.5%

(25/218)

24.8%

(30/121)

TLR

6.0%

(13/218)

20.7%

(25/121)

Non-TLR

7.8%

(17/218)

7.4%

(9/121)

1-Year

ARC

Stent

Thrombosis

Definite

or

Probable

0.5%

(1/215)

0.8% (1/119)

Definite

0.5%

(1/215)

0.8%(1/119)

Probable

0.0%(0/215)

0.0%

(0/119)

b

DES

Control

2.

Effectiveness

Results

The

analysis

of

effectiveness

was

based on

the

224

evaluable

subjects

at

the

9-

month primary

endpoint.

Key

safety

and

effectiveness

outcomes

are

presented

in

Tables

21

through

26.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

43

Table

21:

PERSEUS

Small

Vessel

Clinical

Results

1

year

(ITT

population)

ION

Stent

Historical Control

Express

(N=224)

BMS

(N=125)

EFFICACY

TVR, Overall

11.5%

(25/218)

24.8%

(30/121)

TLR,

Overall

6.0%

(13/218)

20.7%

(25/121)

TLR,

PCI

5.5%

(12/218)

19.0%

(23/121)

TLR,

CABG

0.5%

(1/218)

1.7%

(2/121)

Non-TLR,

Overall

7.8%

(17/218)

7.4%

(9/121)

Non-TLR,

PCI

7.3%

(16/218)

6.6%

(8/121)

Non-TLR,

CABG

0.5%

(1/218)

0.8%

(1/121)

SAFETY

Total

Death

1.4%

(3/218)

1.7%

(2/121)

Cardiac

Death

or

MI

2.3%

(5/218)

3.3%

(4/121)

Cardiac

Death

1.4%

(3/218)

0.8%

(1/121)

MI

0.9%

(2/218)

2.5%

(3/121)

Q-wave

MI

0.5%

(1/218)

0.0%

(0/121)

Non-Q-wave

MI'

0.5%

(1/218)

2.5%

(3/121)

ARC

Stent Thrombosis

Definite

or

Probable

0.5%

(1/215)

0.8% (1/119)

Definite

0.5%

(1/215)

0.8%

(1/119)

Probable

0.0%

(0/215)

0.0%

(0/119)

a

Non-Q-wave

MI

timing: Events occurred

at

day

218

post-procedure

in

the

ION

Stent

group

and

at

days

0,

8,

and

187

post-procedure

in

the

historical

BMS

control

group.

Abbreviations:

ARC=Academic

Research

Consortium; BMS=bare

metal

stent;

CABG=coronary

artery

bypass

graft;

MI=myocardial

infarction;

PCI=percutaneous

coronary intervention;

TLR-target

lesion

revascularization;

TVR=target

vessel

revascularization.

This

trial

was not sized to

determine

the

rate

of

low

frequency events

with

a

pre-specified

precision.

Table

22:

PERSEUS

Small

Vessel

Primary

Endpoint

Historical

9-Mnth

Ie

IOM

Tm

Stent

Control

Difference

P

Value

sse

L(N=224)

Express

BMS

195%

CII

(N=125)

Intent-to-Treat

a

038±0.51

(197)

0.80±0.53

(108) -0.42

[-0.54,

-0.30]

<0.0001

(-0.38,

2.28)

(-0.15,

2.10)

Propensity

score

0.37

0.81

-0.45[

-0.59,

-0.31]

<0.000

1

adjusted

I

a

Primary

analysis

set

for

assessing

hypothesis

of

superiority

and

study

success criterion.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

44

-

Table

23:

PERSEUS

Small

Vessel

Secondary

Endpoint

Performance

ION

Stent

Upper

95%

12-Month

TLF

Confidence

P

Value

Goal

(N=224)Limit

Intent-to-Treata

19.5%

7.34%

10.80%

<0.0001

1_

(16/218)

a

Primary

analysis

set

for

assessing

hypothesis

of

superiority

and

study

success

criterion.

Table

24:

PERSEUS

Small

Vessel

Angiographic

Results

Historical Control

N=197

teExpress

BMS

Angiographic

Outcomes

a

(N=108)

MLD

(mm),

In-stent

Post-Procedure

2.11±0.21

(197)

2.09±0.30

(108)

9-Month

1.73±0.53

(197)

1.29±0.55

(108)

MLD

(mm),

Analysis

Segment

Post-Procedure

1.70±0.29

(197)

1.76±0.38

(108)

9-Month

1.50±0.48

(197)

1.22±0.50

(108)

Acute

Gain

(mm),

In-stent

1.57±0.27

(197)

1.47±0.33

(108)

Acute

Gain,

Analysis

Segment

(mm)

1.16±0.30

(197)

1.14±0.39

(108)

%

DS,

In-stent

Post-Procedure

0.31±10.76

(197)

6.63±10.97

(108)

9-Month

18.48±23.31

(197)

40.72±23.64

(108)

%

DS,

Analysis

Segment

Post-Procedure

20.12±9.42

(197)

22.34±10.69

(108)

9-Month

29.82±19.82

(197)

43.85±21.44

(108)

Late

Loss,

In-stent

(mm)

0.38±0.51

(197)

0.80±0.53

(108)

Late

Loss,

Analysis

Segment

(mm)

0.21±0.41

(197)

0.53±0.52

(108)

Binary

Restenosis

In-stent

restenosis

11.7%

(23/197)

34.3%

(37/108)

Analysis

segment

restenosis

13.7%

(27/197)

38.0%

(41/108)

a

Includes

all

subjects

with

paired

lesion

data.

Abbreviations:

BMS=bare

metal

stent;

DS=diameter

stenosis;

MLD=minumum

lumen

diameter.

Table

25:

PERSEUS

Small

Vessel

Stent

Thrombosis

Historical

Control

N=2

StntExpress

BMS

Intent-to-Treat

Population

(N=125)

Protocol

Defined

Stent

Thrombosis

Cumulative

through

I

year

0.5%

(1/215)

0.8%

(1/119)

Acute

ST

(<24

hrs)

0.0%

(0/224)

0.0%

(0/125)

Subacute

ST

(>24

hrs

and

530

days)

0.0%

(0/221)

0.8%

(1/125)

Late

ST

(>30

days

and

12

months)

0.5%

(1/217)

0.0%

(0/124)

ARC

Definite

&

Probable

Stent

Thrombosis

Cumulative

through

1

year

0.5%

(1/215)

0.8% (1/119)

Acute

ST

(524

hrs)

0.0%

(0/224)

0.0%

(0/125)

Subacute

ST

(>24

hrs

and

530 days)

0.0%

(0/221)

0.8%

(1/125)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

45

Table

25:

PERSEUS

Small

Vessel

Stent

Thrombosis

Late

ST

(>30

days

and

<12

months)

0.5%

(1/217)

0.0%

(0/124)

See

definitions

provided

with Table

18

Numbers

are

%

(Count/Sample

Size).

This

trial

was

not

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Abbreviations:

BMS=bare

metal

stents;

ST=stent

thrombosis.

Figure

5:

PERSEUS

Small

Vessel

Cumulative

Frequency

Distribution

of

9-Month

In-Stent

Late

Loss

by

QCA,

Intent-to-Treat,

All

Angiographic

Subset

Subjects

(N=349)

100

-

80 -______

_o

*** sus

--

Stent

Express

_

60

-

___

_

(N=197)

.

(N=108)

------------ .----

Median

0.21 0.72

1

Minimum

-0.38

-0.15

40

-

Maximum

2.28

2.1

Mean

0.38

0.80

20

Standard

Deviation

0.51

0.53

Coefficient

of

Var.

135.19%

65.95%

0

20

40

60

80

100

Observed

Value

Results

in

subjects

with

and

without

diabetes:

Table

26

shows

1-year

outcomes

in

subjects with

and

without medically

treated

diabetes (defined

as

treatment

with

oral

hypoglycemic

agents

or

insulin

at

enrollment).

The

PERSEUS

SV

study

was

not

stratified

for

diabetic status,

was

not adequately

powered

to

study safety

or

effectiveness

of

the

BMS

Express

Stent

versus the

ION

Stent

in

subjects

with

or

without

diabetes,

and

was

not

designed

to

specifically support

an

approval

for use

in

diabetic

subjects.

These

exploratory

analyses

suggest

that

in

subjects

treated with

the

ION

Stent,

1-year

TLR

rates

were

6.2%

in

diabetic

and

5.8%

in

non-diabetic

subjects,

and

lower

compared

to

the

historical

BMS

Express

control.

Table

26:

PERSEUS

Small

Vessel

Clinical

Results

in

Subjects

with

and

Without

Medically

Treated

Diabetes

I-year

(ITT

Population)

ION

Stent

Subjects

With

ION

Stent

Subjects

Medically

Treated

Without

Medically

Diabetes

Treated

Diabetes

(N=82)

(N=

142)

EFFICACY

TVR,

Overall

9.9%

(8/81)

12.4%

(17/137)

TLR,

Overall

6.2%

(5/81) 5.8%

(8/137)

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

46

Table

26:

PERSEUS

Small

Vessel

Clinical

Results

in

Subjects with

and

Without

Medically

Treated

Diabetes

I-year

(ITT

Population)

ION

Stent

Subjects

With

ION

Stent

Subjects

Medically

Treated

Without

Medically

Diabetes

Treated

Diabetes

(N=82)

(N=142)

TLR,

PCI

6.2%(5/81)

5.1%

(7/137)

TLR,

CABG

0.0%(0/81)

0.7%

(1/137)

Non-TLR,

Overall

6.2%

(5/81)

8.8%

(12/137)

Non-TLR,

PCI

6.2%

(5/81)

8.0%

(11/137)

Non-TLR,

CABG

0.0%

(0/81)

0.7%

(1/137)

SAFETY

Total

Death

2.5%(2/81)

0.7%

(1/137)

Cardiac

Death

or

MI

3.7%

(3/81)

1.5%

(2/137)

Cardiac

Death

2.5%

(2/81)

0.7%

(1/137)

MI

1.2%(1/81)

0.7%

(1/137)

Q-wave

MI

1.2%(1/81)

0.0%

(0/137)

Non-Q-wave

MI

0.0%

(0/81)

0.7%

(1/137)

ARC

Stent

Thrombosis

Definite

or

Probable

1.3%

(1/79)

0.0%

(0/136)

Definite

1.3%(1/79)

0.0%

(0/136)

Probable

0.0%(0/79)

0.0%

(0/136)

This

trial

was

not

sized

to

determine

the rate

of

low

frequency

events

with

a

pre-specified

precision.

Abbreviations:

ARC=Academic

Research

Consortium;

CABG=coronary

artery

bypass

graft;

DES=drug-eluting

stent;

MI=myocardial

infarction;

PCI=percutaneous

coronary intervention;

TLR-target

lesion

revascularization;

TVR=target

vessel

revascularization.

C.

PERSEUS

Clinical

Trial

Program

-

Sex/Gender

Analyses

PERSEUS

Workhorse

To

evaluate

for

possible

sex-based

differences

in

outcome

of

treatment

with

the

ION

Stent,

sex/gender-specific

analyses

were

performed

on

safety

and

effectiveness

endpoints.

The

results

suggest

that

the

general

conclusions

of

the

overall

study

regarding

both

safety

and

effectiveness

can

be

generalized

for

males

and

females.

In

the

PERSEUS

Workhorse

ITT

population,

of

the

942

subjects

randomized

to

ION,

667

subjects

were male

(70.8%)

and

275

subjects

were

female

(29.2%).

The

proportions

in

the

TAXUS

Express

group

were

similar

(68.8%

male,

31.2%

female).

In

comparison,

the

prevalence

of

coronary

artery

disease

(CAD)

is

estimated

at

9.2

million

in

males

and

8.4

million

in

females

for

adults

age

20

and

older

the

United

States

(i.e.,

the

CAD

population

is

estimated

to be

52.2%

males

and

47.7%

females).

The

disproportionate

enrollment

distribution

in

this

trial

may

be

partly

attributable

to

gender

differences

in

symptoms

and

pathophysiology

5

,

which

may

lead

to

under-

diagnosis

and

referral

of

female

subjects

with

CAD.

The

gender

proportions

enrolled

in

this

trial

are

similar

to

other

drug-eluting

stent

trials;

a

meta-analysis

of

paclitaxel-

eluting

stent clinical

trials

reported

an

overall

gender

distribution

of

71.8%

male

and

28.2%

female.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

47

The

PERSEUS

WH

study

was

not powered

to

study

safety

or effectiveness

of

the

ION

Stent

versus

the

TAXUS

Express

Stent

in

sex-specific

subgroups.

PERSEUS

WH

primary

and

secondary

endpoint

data

were

assessed

for

differences

between

male

and

female

subgroups,

as

well

as

for

any

interaction

between

treatment

group

and

gender.

These

post

hoc

analyses

suggest

that

in

subjects

treated

with

the

ION

stent,

12-month

TLF rates

were

7.0%

in

females

and

5.1%

in

males,

and

9-month

%DS

was

26.95±18.62

in

females

and

25.71±17.32

in

males.

Numerical

differences

were

observed

in

the

treatment

effect

(i.e.,

the

difference

between

the

ION

Stent

and

TAXUS

Express

Stent),

as

shown

in

Table

27

below.

No

significant

treatment-by-gender

interaction

effect

was

observed

for the

primary

endpoint

of

12-month TLF

(P=0.5485).

A

marginally

significant

treatment-by-gender

interaction

effect

was

observed

for

the

secondary

endpoint

of

9-month

in-segment

%DS

under

the

natural

log

transformation

(P=0.0628).

However,

this analysis

is

limited

by

the small

sample

size;

fifteen

(15)

female

TAXUS

Express

subjects

have

available

9-month

in-segment

%DS

data,

and

the

mean

%DS

for

those subjects

was

markedly

low.

Considering

the small

sample

size

and

the

lack

of

observed

interaction

effect

for

the

primary

endpoint

of

12-month

TLF,

there

does

not

appear

to

be

a

clinically

significant

treatment-by-gender

interaction

in

the

PERSEUS

WH

trial.

This

suggests

that

the

overall

conclusions

of

this

trial

regarding

both

safety

and

effectiveness

of

the

ION

Stent

can

be

generalized

for

males

and

females.

Table

27:

PERSEUS

Workhorse

Primary

and

Secondary

Endpoint

Results

by

Gender,

Intent-to-Treat,

All

Subjects

(N=887)

Relative

Risk

Difference

Interactio

TAXUS

Express

ION

Stent

[95%

Cl]

[95%

Cl]

P

value

n

p-Value

12-month

TLF

(Primary

Endpoint)

(N=220)

(N=667)

_______

-

(N=22)

(N667)

1.09

[0.54,

0.4%

[-2.9%,

Male

4.7%

(10/214)

5.1%

(33/650)

.17]

3%]

0.8136

(N=100)

(N=275)

21]37]058

(N=10)

(N=75)

-0.77

[0.36,

-2.1%

[-8.5%,

Female

9.1%(9/99)

7.0%

(19/272)

1.6

4%]

0.4971

1.64]

4.3%]

9-month

Percent

Diameter

Stenosis

In-Segment

(Secondary

Endpoint)

(N=53)

(N=180)

28.57±19.16

(46)

25.71±17.32

Male

(7.56,

100.00)

(156)

NA

-2.86

[-8.70,

2.97]

0.3373

(3.31,

100.00)

0.0628

(N=21)

(N=76)

26.95±18.62

Female

19.71

1)

(72)

NA

7.34

[-2.29,

16.97]

0.1389

(9.71,

31.66)

(42,9.9

______

_

______

(4.22,

95.29)

Table

28

shows

12-month

clinical

results

in

male

and

female

subjects.

PMA P100023:

FDA

Summary

of

Safety and

Effectiveness Data

Page

48

Table

28:

PERSEUS

Workhorse

12-Month

Clinical

Endpoints,

All

ION Male

and

Female

Subjects,

Intent-to-Treat

(N=942)

ION

Male

Stent

Subjects

ION

Female

Stent Subjects

Endpoint

(N=667)

(N=275)

EFFICACY

TVR,

Overall

5.7%

(37/650)

5.5%

(15/272)

TLR,

Overall

3.4%

(22/650)

4.8%

(13/272)

TLR,

PCI

3.2%

(21/650)

4.4%

(12/272)

TLR,

CABG

0.3%

(2/650)

0.4%

(1/272)

Non-TLR,

Overall

2.8%

(18/650)

1.8%

(5/272)

Non-TLR,

PCI

2.5%

(16/650)

1.8%

(5/272)

Non-TLR,

CABG

0.5%

(3/650)

0.0%

(0/272)

SAFETY

Total

Death

0.8%

(5/650)

0.4%

(1/272)

Cardiac

Death

or MI

2.3%

(15/650)

2.9%

(8/272)

Cardiac

Death

0.6%

(4/650)

0.4%

(1/272)

MI

2.0% (13/650)

2.6%

(7/272)

Q-wave

MI

0.5%

(3/650)

0.7%

(2/272)

Non-Q-wave

MI

1.5%

(10/650)

1.8%

(5/272)

ARC Stent

Thrombosis

Definite

or

Probable

0.6%

(4/647)

0.0%

(0/271)

Definite

0.5%

(3/647)

0.0%

(0/271)

Probable

0.2%

(1/647)

0.0%

(0/271)

Figures

6

and

7

show

the

cumulative

TLF

rate

through

12-months

for males

and

females,

respectively.

This

post-hoc

analysis

suggests

that within

each

sex-specific

subgroup,

non-inferiority

of

ION

to

TAXUS

Express

for

this

endpoint

is

maintained

at

all

follow-up

time-points

(30d,

90d,

180d,

270d,

360d).

Figure

6:

PERSEUS

Workhorse

Cumulative

Rate of

Target

Lesion

Failure

to

12

Month,

All

Male

Subjects,

Intent-to-Treat,

Event

Rate

+

1.5

SE

(N=887)

20

-

TAXUS

Express

Stent

(N=220)

ION

Stent

(N=667)

E

15

-

10

>

5.0%

w

u_

5

4.6%

0

30

60

90

120 150

180

210

240

270

300

330

360

390

Days

Since

Index Procedure

TAXUS

Express

Stent:

220

214 213 212 212

211 211 211

208

ION

Stent: 667

653

650

647 647 646

642

638

631

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

49

Figure

7:

PERSEUS

Workhorse

Cumulative

Rate of

Target

Lesion

Failure

to

12

Month,

All

Female

Subjects,

Intent-to-Treat,

Event

Rate

+

1.5

SE

(N=375)

20

-

TAXUS

Express

Stent

(N=100)

ION

Stent

(N=275)

g 15

C

>

6.9%

LLL

10

-

.2

0

30 60

90

120 150

180

210

240

270

300

330

360

390

Days Since

Index

Procedure

TAXUS

Express

Stent:

100

97

97 97

96

95

94

93

ION

Stent: 275

268

268 267

266

264

263

262

256

PERSEUS

Small

Vessel

To

evaluate

for

possible

sex-based differences

in

outcome

of

treatment

with

the

ION

Stent

when used

in

small

vessels,

sex/gender-specific

analyses

were

performed

on

safety

and

effectiveness

endpoints.

The

results

suggest

that

the

general

conclusions

of

the

overall

study

regarding

both

safety

and

effectiveness

can

be

generalized

for

males

and

females.

In

the

PERSEUS

Small

Vessel

ITT

population,

of

the 224

registry

subjects,

143

subjects

were

male

(63.8%)

and

81

subjects

were

female

(36.2%).

The

proportions

in

the

BMS

Express

historical

control

group

were

similar

(60.8%

male,

39.2%

female).

In

comparison,

the

prevalence

of

coronary

artery

disease

(CAD)

is

estimated

at

9.2

million

in

males

and

8.4

million

in

females

for

adults

age

20

and

older

the

United

States

(i.e.,

the

CAD

population

is

estimated

to be

52.2%

males

and

47.7%

females).

The

disproportionate

enrollment

distribution

in

this trial may

be

partly

attributable

to

gender

differences

in

symptoms

and

pathophysiology

5

,

which

may

lead

to

under-

diagnosis

and

referral

of

female

subjects

with

CAD.

The

gender

proportions

enrolled

in

this

trial

are

somewhat

more

representative

of

the

disease prevalence

than

the

Workhorse

trial

(70.8%

male;

29.2%

female)

and

other

drug-eluting

stent

trials.

This

may

be

due in

part

to

the

smaller

average

reference

vessel

diameter

in

female

subjects

6

.

The

PERSEUS

SV

study

was

not

powered

to

study

safety

or effectiveness

of

the

ION

Stent

in

sex-specific

subgroups.

PERSEUS

SV

primary

and

secondary

endpoint

data

were

assessed

for

differences

between

male

and

female

subgroups,

as

well

as

for

any

interaction

between

treatment

group

and

gender.

These

post

hoc

analyses

suggest

that

in

subjects

treated

with

the

ION

stent

in

small

vessels,

9-month

in-segment

late

loss was

0.41+0.48

in

females

and

0.36±0.52

in

males,

and

12-month TLF

was

5.0%

in

females

and

8.7%

in

males.

In

the

BMS

Express

historical

control

group,

rates

of

12-month

TLF

were also

numerically

higher

in

males

(25.2%)

than

females

(16.8%).

These

observations

are

limited

by

the

small

sample

size

available

for

these analyses.

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

50

Treatment

effect

(i.e.,

superiority

of

ION

Stent

to

historical

control

BMS)

was

demonstrated

for

both

males

and

females,

as

shown

in

Table

29

below.

No

significant

treatment-by-gender

interaction

effect

was

observed

for the

primary

endpoint

of

9-month

in-stent

late

loss

(P=0.7255)

or

12-month

TLF

(P=0.9246).

This

suggests

that

the

overall

conclusions

of

this

trial

regarding

both

safety

and

effectiveness

of

the

ION

Stent

in

small

vessels

can

be

generalized

for

males

and

females.

Table

29:

PERSEUS

Small

Vessel

Primary

and

Secondary

Endpoint

Results,

by

Gender,

Intent-to-Treat,

All

Subjects

(N=219)

Historical

Relative

Risk

Difference

Interactio

Control

BMS

ION

Stent

[95%

CI]

[95%

CI]

P

value

n

p-Value

9-month

Late

Loss

In-Stent

(Primary

Endpoint)

(N=76)

(N=143)

0.36±0.52

Male

08±54

(0)

(127)

NA

-0.44

[-0.59,

-0.28]

<.0001

(-0.38, 2.28)

0.7255

(N=49)

(N=81)

Female

0.80±0.50

(38)

0.41±0.48

(70)

NA

-0.39

[-0.59,

-0.20]

0.0001

(-0.09,

2.10)

(-0.34,

1.59)

1

12-month

TLF

(Secondary

Endpoint)

(N=76)

(N=143)

Male

25.7%

(19/74)

8.7%

(12/138)

0.34

[0.17,

0.66]

-17.0%

[-28.0%,

-6.0%]

0.0009

0.9246

(N=49)

(N=81)

Female

17.0%

(8/47)

5.0%

(4/80)

0.29

[0.09,

0.92]

-12.0%

[NA]

0.0549*

Table

30

shows

12-month

clinical

results

in

male

and

female

subjects.

Table

30:

PERSEUS

Small

Vessel

12-Month

Clinical

Endpoints,

All

ION

Male

and

Female

Subjects,

Intent-to-Treat

(N=224)

ION

Male

Stent

Subjects

ION

Female

Stent

Subjects

Endpoint

(N=143)

(N=81)

EFFICACY

TVR,

Overall

13.8%

(19/138)

7.5%

(6/80)

TLR,

Overall

7.2%

(10/138)

3.8%

(3/80)

TLR,

PCI

6.5%

(9/138)

3.8%

(3/80)

TLR,

CABG

0.7%

(1/138)

0.0%(0/80)

Non-TLR,

9.4%

(13/138)

5.0%

(4/80)

Overall

PCI

Non-TLR,

8.7%

(12/138)

5.0%(4/80)

CABG

Non-TLR,

0.7%

(1/138)

0.0%(0/80)

SAFETY

Total Death

1.4%

(2/138)

1.3%(1/80)

Cardiac

Death

or

MI

2.9%

(4/138)

1.3%

(1/80)

Cardiac

Death

1.4%

(2/138)

1.3%

(1/80)

MI

1.4%

(2/138)

0.0%(0/80)

Q-wave

MI

0.7%

(1/138)

0.0%

(0/80)

PMA P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

51

ION

Male

Stent

Subjects

ION

Female

Stent

Subjects

Endpoint

(N=143)

(N=81)

MI

Non-Q-wave

0.7%

(1/138)

0.0%

(0/80)

ARC Stent

Thrombosis

Definite

or

Probable

0.7%

(1/136)

0.0%

(0/79)

Definite

0.7%

(1/136)

0.0%(0/79)

Probable

0.0%

(0/136)

0.0%

(0/79)

In

the

PERSEUS

SV

Trial, the study

success

criterion

for

12-month TLF

was

met

for

both

sexes

(greater

than

performance

goal

of

19.5%).

Figures

8

and

9

show

the

cumulative

TLF

rate

through

12-months

for

males

and

females,

respectively.

This

post-hoc

analysis

suggests

that within

each

sex-specific

subgroup,

the

ION

group

had

lower

TLF

rates

than

the BMS

Express

historical

control

group

at

all

follow-up

time-

points

(30d,

90d,

180d,

270d,

360d),

although

confidence

intervals

are

wide

and

overlap

at

earlier

time

points.

Figure

8:

PERSEUS

Small

Vessel

Cumulative

Rate

of

Target

Lesion

Failure

to

12

Month,

All

Male

Subjects,

Intent-to-Treat,

Event Rate

±

1.5

SE

(N=219)

30

BMS

Express

(N=76)

ION

Stent

(N=143)

:

25.2%

0

L

10

8.7%

U-

-J~

0

30

60

90

120

150 180

210 240 270

300

330

360

390

Days

Since

Index

Procedure

BMS:

76

76 76

76

74

72

71

67

ION

Stent:

143

141

138 138

138 137

137

136

130

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

52

Figure

9

PERSEUS

Small

Vessel

Cumulative

Rate

of

Target

Lesion

Failure

to

12

Month,

All

Female

Subjects,

Intent-to-Treat,

Event

Rate

±

1.5

SE

(N=130)

30

BMS

Express

(N=49)

ION

Stent

(N=81)

0

20

--

C

20

16.8%

0)

I

Ili

lI

S10

U-

-

7

5.0%

0

30 60

90

120 150

180

210

240 270

300

330 360

390

Days

Since

Index

Procedure

BMS:

49

46 46 45

45 44

43

41

ION

Stent:

81

79

79 79

79

78

X.

PANEL

MEETING

RECOMMENDATION

AND

FDA'S

POST-PANEL

ACTION

In

accordance

with

the

provisions

of

section

515(c)(2)

of

the

Act

as

amended

by

the

Safe

Medical

Devices

Act

of

1990,

this

PMA

was

not referred

to

the

Circulatory

Systems

Devices

Panel,

an

FDA

advisory

committee,

for

review

and

recommendation

because the

information

in

the

PMA

substantially

duplicates

information

previously

reviewed

by

this

panel.

XI.

CONCLUSIONS

DRAW

FROM

PRECLINICAL

AND

CLINICAL

STUDIES

The safety

and

effectiveness

of

the

ION

Paclitaxel-Eluting

Platinum

Chromium

Coronary

Stent

System

(Monorail

and

Over-The-Wire)

is

based

on the

results

obtained

from:

evaluation

of

biocompatibility;

characterization

of

in

vivo

pharmacokinetics;

in

vitro

engineering

testing;

coating

characterization;

chemistry,

manufacturing

and

controls

information;

in

vivo

animal

testing;

sterilization

information;

stability

testing;

and

clinical

studies.

These

tests revealed

the

following:

A.

Safety

Conclusions

The

biocompatibility,

in

vivo

pharmacokinetics,

and

in

vivo

animal

testing

conducted

demonstrate that

the

acute

and

chronic

in

vivo

performance

characteristics

of

the

product

provide

reasonable

assurance

of

safety

and

acceptability

for

clinical

use.

The

in

vitro

engineering

testing

conducted

on

the

stent

and

delivery

system(s)

demonstrated

that

the

performance characteristics

met

the

product

specifications

and

the

coating

characterization testing adequately

described

the

important attributes

of

the

paclitaxel/polymer

coating.

The

chemistry,

manufacturing,

and

controls information

ensures

that

product

meeting

specifications

will

be

released.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

53

The

test

results

obtained

from

the

sterilization

testing

demonstrated

that

the

product

can

be

adequately

sterilized

and

is

acceptable

for

clinical

use.

The

stability

testing

demonstrated

that

the

product

can

be

labeled

with

a

shelf

life

of

18

months.

The

results

of

the

PERSEUS

Clinical

Trial

Program

showed

that

the

principal

adverse

events

rates for

the

ION

were

similar

to

those

observed

for

the

TAXUS

Express

control

group.

Although

an

angiographic

core

laboratory

review

of

all

available

angiograms

revealed

a

total

of

3

stent

fractures

-

2

ION

stent

fractures

(Type

33

fractures

that

were

seen

on

angiograms

performed

at 286

and

259

days

post-stent

implantation,

respectively)

and

1

Taxus Express

stent fracture

(Type

43

fracture

noted

on

an

angiogram

performed

861

days

post-stent

implantation).

Only

the fracture

that

occurred

with the

Taxus Express

stent

was

associated

with

a

major

adverse

cardiovascular

event

(a

TLR).

B.

Effectiveness

Conclusions

PERSEUS

Workhorse

The

effectiveness

of

ION

workhorse

stents

was based

on the

rate

of

target

lesion

failure

(TLF)

at

12

months

post-index

procedure,

testing

non-inferiority

of

the

ION

Stent

relative

to

the

TAXUS

Express

Paclitaxel-Eluting

Stent

control.

In-segment

percent

diameter

stenosis

at

9

months

post-index

procedure

as

measured

by

quantitative

coronary

angiography

(QCA)

is

the

secondary

endpoint.

The

prespecified

Bayesian

analyses

showed

that

there

was

a

99.96%

Bayesian

posterior

probability

that

the

ION

stent

was

non-inferior

to

the

TAXUS

Express

stent,

demonstrating

non-inferiority

of

the

ION

stent

versus

the

TAXUS

Express

stent.

PERSEUS

Small

Vessel

The

effectiveness

of

the

ION

small

vessel

stents

was

established

by

measuring

in-stent

late

loss

by

QCA

at

9-months

(primary

endpoint)

as

well

as

TLF

at

12

months

as

compared

to

a

performance

goal

(secondary

endpoint,

based

on

TAXUS

Express

Stent

results

from

the

TAXUS

IV

and

TAXUS

V

trials).

The

study

success

criteria

are

met

when

mean

in-stent

late

loss

at

9

months

post-index

procedure

for

the

ION

Stent group

is

shown

to be

superior

to

that

of

the

historical

control

and

the

12-month

TLF

rate

for

the

ION

Stent

group

is

shown

to

be

less

than

the

performance

goal.

The

analyses

showed

that

the

ION

small

vessel

stents

were

superior

(p-value

<0.0001)

to

both

the

in-stent

late

loss

historical

control

at

9

months

and

TLF

rate

at

12

months.

C.

Overall

Conclusions

The

clinical

testing

conducted

demonstrated

that

the

IONTM

Paclitaxel-Eluting

Coronary

Stent

Systems

(Monorail

and

Over-The-Wire)

provides

a

reasonable

assurance

of

safety

and

effectiveness

when

used

as

indicated

in

accordance

with

the

instructions

for use.

XII.

CDRH

DECISION

CDRH

issued

an

approval

order

on

April

22, 2011.

The final

conditions

of

approval

cited

in

the

approval

order

are

described

below.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

54

1.

BSC

should

collect

and

report

to

the

Agency

on

an

annual

basis,

clinical

outcomes

through

5

years

post-procedure

on

at

least

80%

of

patients

enrolled

(excluding

those

discontinued

due

to

death)

in

the

PERSEUS

Workhorse

and

PERSEUS

Small

Vessel

studies.

When

appropriate

or

as

requested

by

FDA,

BSC

should

submit

PMA

supplements

requesting

approval

to

update

your

Instructions

for

Use

(IFU)

to

include

these

data.

2.

BSC

should

collect

clinical

data

on

the

implantation

of

the

PMA-approved,

commercially

distributed

ION

product

in

the

U.S.

The

trial

should

be

statistically

powered

to

evaluate

the

annual

rates

of

stent

thrombosis,

and

the

rate

of

cardiac

death

plus

myocardial infarction

(MI)

through

five

years

in

patients treated

with

the

ION

product

according

to

its

labeled

indications.

These data

are

needed

to

evaluate

whether

the

rate

of

stent

thrombosis

plateaus

or

increases

over

time,

and

to

evaluate

the

impact

of

stent

thrombosis

on

rates

of

cardiac death

and

MI.

These

data

are

also

needed

to

evaluate

the

potential

for

rare

adverse events related

to

the

drug substance

and/or

drug

carrier

that could

not

be

detected

in

your

initial

clinical

trials.

BSC

has

proposed

collecting

these data

from

at

least

2,500

patients

at

up

to

50

U.S.

sites

in

the

ION

Postmarket

Registry.

FDA

agrees

that

the

registry

protocol

submitted

in

the

original

PMA

is

acceptable.

Please

provide

progress

reports

at

6,

12,

18,

and

24

months

and

annually

thereafter

through

5

years

with

data

from

your

U.S.

registry.

When

appropriate

or

as

requested

by

FDA,

BSC

should

submit

PMA

supplements

requesting

approval

to

update your

IFU

to

include these

data.

Please

note

that

if

subsequent

data analyses identify

areas

of

significant

off-label

use,

the

firm

should

submit

an

IDE

to

conduct

an

appropriate

study

to

evaluate

the

off-label

use.

3.

The

issue

of

the

optimal

duration

of

dual

antiplatelet

therapy following

PCI

with

drug-eluting

stents

(DES)

remains

a

critical

question

that

is

currently

being studied

in

the

DAPT

trial.

FDA

acknowledges

that

BSC

is

participating

in

this

trial

to

address

a

condition

of

approval

for

the

Taxus

Liberte

DES

(P060008).

As

the

duration

of

dual

antiplatelet

therapy

is

also

relevant

for

the

ION

Paclitaxel-Eluting

Coronary

Stent, the

sponsor

should

fulfill

their commitment

to

the

condition

of

PMA

approval

for

P060008.

When

appropriate

or

as

requested

by

FDA,

BSC

should

submit

PMA

supplements

to

the

ION

PMA

(P100023)

requesting

approval

to

update

their

IFU

to

include

the

data

collected

in

the

DAPT

trial.

If

BSC

does not

fulfill

the

condition

of

approval

for

P060008,

they

should

conduct

or

participate

in

a

separate clinical

trial

that

will

develop

data

to

study

the

duration

of

dual

antiplatelet therapy

following

implantation

of

the

ION

DES

and

subsequently

submit PMA

supplements

to

this

PMA requesting

approval

to

include

these data

in

an

IFU

update.

4.

BSC

has agreed

to

provide

annual

stability

data

for

their

Maple

Grove

manufacturing

site

as

part

of

their

annual

reports.

The

applicant's

manufacturing

facilities

were

inspected

and

found

to be

in

compliance

with

the

device

Quality System

(QS)

regulation

(21

CFR

820).

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

55

XIII. APPROVAL

SPECIFICATIONS

Directions

for

use:

See

device

labeling.

Hazards

to

Health

from

Use

of

the

Device:

See

Indications,

Contraindications,

Warnings,

Precautions,

and

Adverse Events

in

the

device

labeling.

Post-approval

Requirements

and

Restrictions:

See

approval

order.

XIV.

REFERENCES

1.

Allocco

DJ,

Cannon

LA,

Britt

A,

Heil

JE,

Nersesov

A,

Wehrenberg

S,

Dawkins

KD,

Kereiakes

DJ.

A

prospective

evaluation

of

the

safety

and

efficacy

of

the

TAXUS

Element paclitaxel-eluting

coronary

stent system

for the

treatment

of

de

novo

coronary

artery

lesions:

Design

and

statistical

methods

of

the

PERSEUS

clinical

program.

Trials.

2010;11(1):1

2.

King

SB,

3rd,

Smith

SC, Jr.,

Hirshfeld

JW, Jr.,

Jacobs

AK,

Morrison

DA,

Williams

DO,

Feldman

TE,

Kern

MJ,

O'Neill

WW,

Schaff

HV,

Whitlow

PL,

Adams

CD,

Anderson

JL,

Buller

CE,

Creager

MA,

Ettinger

SM,

Halperin

JL,

Hunt

SA,

Krumholz

HM,

Kushner

FG,

Lytle

BW,

Nishimura

R,

Page

RL,

Riegel

B,

Tarkington

LG,

Yahcy

CW.

2007

Focused

Update

of

the

ACC/AHA/SCAI

2005

Guideline Update

for

Percutaneous

Coronary

Intervention:

a

report

of

the

American College

of

Cardiology/American

Heart

Association

Task

Force on

Practice

Guidelines:

2007

Writing

Group

to

Review New

Evidence

and

Update

the

ACC/AHA/SCAI

2005

Guideline Update for

Percutaneous

Coronary Intervention, Writing

on

Behalf

of

the

2005

Writing

Committee. Circulation.

2008;

117(2):261-95.

3.

From

Table

1

in

Popma,

JJ,

Tiroch,

K,

Almonacid,

A,

Cohen,

SA,

Kandzari,

DE,

and

Leon,

MB.

A

Qualitative

and

Quantitative

Angiographic

Analysis

of

Stent

Fracture

Late

Following

Sirolimus-Eluting

Stent

Implantation.

Am

J

Cardiol

103:

923-929,

2009.

4.

Cutlip

DE,

Windecker

S,

Mehran

R,

et

al.

Clinical

End

Points

in

Coronary

Stent

Trials:

A

Case for

Standardized Definitions. Circulation.

2007;115(17):2344-2351.

5.

Shaw

LJ,

Bairey

Merz

CN,

Pepine

CJ,

et

al.

Insights

From

the

NHLBI-Sponsored

Women's

Ischemia

Syndrome

Evaluation

(WISE)

Study:

Part

1:

Gender Differences

in

Traditional

and

Novel

Risk Factors,

Symptom

Evaluation,

and

Gender-Optimized

Diagnostic

Strategies.

J

Am

Coll

Cardiol

2006

47:

S4-20.

6.

Lansky

AJ,

Costa

RA,

Mooney

M,

et

al.

Gender-Based

Outcomes After

Paclitaxel-

Eluting Stent

Implantation

in

Subjects With Coronary

Artery

Disease.

J

Am

Coll

Cardiol

2005

45:

1180-5.

PMA

P100023:

FDA

Summary

of

Safety

and

Effectiveness

Data

Page

56