Food and Drug Administration (FDA)

1
Food and Drug Administration (FDA) Circulatory
System Devices Panel Gaithersburg, Maryland (USA)
7-8 December, 2006
Key Takeaways
This presentation is for information purposes
only and is intended to be used in its entirety
2
FDA confirms the benefits of the TAXUS Stent are
proven, and outweigh any potential risks
FDA Advisory Panel supports the benefits of
Drug-Eluting Stents
Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
3
FDA confirms the benefits of the TAXUS Stent are
proven1, and outweigh any potential risks

• The benefits of the TAXUS Stent outweigh any
  risks
• There is no statistically significant difference
  in ST between TAXUS Stent and BMS control using
  any definition
• There is no difference in death and MI between
  TAXUS Stent and BMS control
• The benefits of the TAXUS Stent extend to high
  risk patients / lesions approved per indication
• Real World use of the TAXUS Stent in highly
  complex patients is in line with historical
  comparators of CABG and PCI

1. Data presented by Dr. Don Baim to FDA Advisory
Panel, The data presented at the Panel was mostly
focused on TAXUS Express2 stent December 2006.
TAXUS Liberté Stent is not approved for use in
patients with coronary artery reference vessel
diameters lt 2.25mm or gt 4.0mm. TAXUS Liberté
Stent is not approved for use in patients with
lesions longer than 32mm. TAXUS Liberté Stent
is contraindicated for stenting of Saphenous Vein
Grafts, in patients with unprotected left main
coronary artery, in patients with heavily
calcified lesions, and in patients with lesions
involving arterial segments with highly tortuous
anatomy. Contents of this slide reflect the
comments and observations from the FDA panel
conducted in December 2006 and are for
information purposes. TAXUS Liberté is not
available for sale in the US.
4
TAXUS Stent has no statistically significant
increase in stent thrombosis by any definition
Rate (No. ST)
1.3 (16) 0.8 (10) p0.24
6 vs 1 ( 0.4) Log-rank p 0.06
Protocol ST
?RD Rate difference
Post-TLR Events Censored
ARC definition presented by Dr Cutlip, TCT 2006
5
TAXUS Stent has no statistically significant
increase in stent thrombosis by any definition
Rate (No. ST)
1.8 (21) 1.1 (13) p0.17
9 vs 3 ( 0.5) Log-rank p 0.08
ARC Def/Prob 1o
1.3 (16) 0.8 (10) p0.24
6 vs 1 ( 0.4) Log-rank p 0.06
Protocol ST
?RD Rate difference
Post-TLR Events Censored
ARC definition presented by Dr Cutlip, TCT 2006
6
TAXUS Stent has no statistically significant
increase in stent thrombosis by any definition
Rate (No. ST)
3.6 (41) 3.5 (39) p0.84
20 vs 22 (- 0.1) Log-rank p 0.79
ARC ALL
1.8 (21) 1.1 (13) p0.17
9 vs 3 ( 0.5) Log-rank p 0.08
ARC Def/Prob 1o
1.3 (16) 0.8 (10) p0.24
6 vs 1 ( 0.4) Log-rank p 0.06
Protocol ST
?RD Rate difference
Post-TLR Events Censored
ARC definition presented by Dr Cutlip, TCT 2006
7
A more meaningful measure of safety may be Death
MI
TAXUS I, II-SR, IV, V Studies (N2,797)
Efficacy
TAXUS Stent is as safe as BMS
plt0.0001
p0.24
p0.78
p0.87
p0.83
p0.17
p0.86
20.2
10.5
4-Yr Cumulative Events ()
8.3
7.9
7.4
7.1
6.9
6.4
1.8
1.1
1.3
1.1
1.0
0.8
Primary ARC ST Def/Prob
Protocol ST
All Death
All MI
Q Wave MI
Death or Q Wave MI
TLR
n13 n21 n10 n16 n79
n75 n80 n82 n12 n13
n89 n86
n133
n266
TAXUS Stent 4-year meta-analysis See Glossary.
Kaplan Meier estimate and p values from log rank
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Clear Benefit of the TAXUS StentSubset Data
Stent Target Lesion Revascularization Rates
TAXUS I, II-SR, IV, V Studies (N2,797)
plt0.0001
plt0.0001
plt0.0001
plt0.0001
plt0.0001
35.9
31.3
27.7
24.9
TLR Rate ()
20.2
14.5
13.4
13.1
12.8
10.5
n965
N2,797
n715
n341

n497
Adapted from Don Baim M.D. - FDA Panel
Presentation December 2006. TAXUS Stent is not
approved for use in patients with coronary artery
reference vessel diameters lt 2.25mm or in
patients with lesions longer than 32mm. TAXUS
Stent 4-year meta-analysis See Glossary. Kaplan
Meier estimate and p values from log rank
9
ARRIVE registry (N 7,393) Complex vs. Simple
Lesions
TVR
p lt0.0001
11.5 (307)
7.2 (98)
ARC definition as presented by Dr Cutlip, TCT
2006. The safety and effectiveness of the TAXUS
Stent have not been established in patients for
longer than 12 months. TAXUS Express² Stent is
not approved for use in patients with coronary
artery reference vessel diameters lt 2.25mm or gt
5.0mm. TAXUS Express² Stent is not approved for
use in patients with lesions longer than 32mm.
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ARRIVE registry (N 7,393) Complex vs. Simple
Lesions
TVR
p lt0.0001
11.5 (307)
7.2 (98)
ARC definition as presented by Dr Cutlip, TCT
2006. The safety and effectiveness of the TAXUS
Stent have not been established in patients for
longer than 12 months. TAXUS Express² Stent is
not approved for use in patients with coronary
artery reference vessel diameters lt 2.25mm or gt
5.0mm. TAXUS Express² Stent is not approved for
use in patients with lesions longer than 32mm.
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FDA Advisory Panel supports the benefits of
Drug-Eluting Stents

• Agreement that the benefits of TAXUS and Cypher
  Stents outweigh any potential risks with on label
  use of DES
• No new recommendation on duration of dual anti
  platelet therapy.
• The Panel felt it was reasonable to endorse the
  ESC and ACC/AHA 12 month guidelines particularly
  in complex patients
• The Panel expressed interest in additional data
  with longer follow up, particularly in higher
  risk patient / lesion groups

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes.
The Cypher Stent is a trademark of JJ Cordis.
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Panel ConsiderationsOn-label use of DES

• Is there a late stent thrombosis issue with DES
  versus BMS?
• The panel had a mixed response to this question.
  After much discussion, the consensus was that
  there may be a very small signal but no
  conclusive answer was given.
• What is the appropriate definition of stent
  thrombosis?
• The ARC definition had a great deal of
  discussion, but there was no consensus about
  using ARC definite plus probable versus
  respective protocol definitions.
• Does the risk of using a DES on label outweigh
  the benefit?
• No, all panel members felt that the benefits
  outweigh the risk.

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
13
Panel Considerations On-label use of DES

• Is there an increase in death and MI with DES?
• The panel agreed no.
• What recommendations should be altered, if any,
  to the duration of dual anti platelet therapy?
• The panel varied widely and was unsure about any
  evidence for extension at this point, but many
  felt it was reasonable to endorse the AHA/ACC 12
  month guidelines. The ESC guidelines are
  consistent with this recommendation.

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
14
Panel Considerations Use of DES in complex
patients / lesions

• Is there a greater risk of LST in more complex,
  real world lesions?
• Most would agree that these more complex patients
  have slightly higher expected and observed rates
  of death and MI, regardless of treatment.
• We DO NOT have contemporary data to indicate
  whether off-label DES use results yield better,
  worse, or the same death and MI outcomes as the
  alternative to bypass surgery.
• Does extended Dual anti-platelet therapy enhance
  patient outcomes?
• Very mixed data, with the strongest evidence
  being the Kaiser data as presented by Dr. Magid
  showing that an extra 3 or 6 months of dual
  therapy beyond the label significantly reduced
  death and MI compared to the label duration
  alone. This is consistent with the Duke landmark
  study published this week in JAMA (Eisenstein, et
  al).
• While the data was somewhat conflicting, the
  panel was leaning towards the AHA/ACC/SCAI
  guidelines of 12 month anti-platelet therapy in
  complex, real world patients. These
  recommendations are consistent with the ESC
  guidelines.

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
15
Panel Considerations Use of DES in complex
patients / lesions

• Is CABG a better option for patients with MV
  disease?
• Surgeons would say yes, and in fact we do not
  have contemporary data beyond the ARTS II study
  to support the non-inferiority of multi-vessel
  drug-eluting stent treatment compared to bypass.
  Hopefully, the randomized SYNTAX trial comparing
  TAXUS stent to CABG in the most complex left
  main and/or 3 vessel disease will provide answers
  to this question.

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
16
Panel ConsiderationsOther comments

• A large focus on education needs to occur. It is
  not just the duty of the FDA to get this
  information out it is everyones
  responsibility.
• Need to get information out to general
  practitioners, patients, dentists, referring
  cardiologists about the importance of Dual
  Anti-Platelet compliance.
• A separate analysis of off label DES utilization
  is required since a higher risk of stent
  thrombosis may exist in these sub groups based on
  data from real world analysis.
• Medtronic presented the Endeavor data and argued
  that all DES are not created equal we would
  agree. Under the ARC definition the Endeavor
  program does show stent thrombosis to include
  late stent thrombosis.
• Abbott also presented an update using preclinical
  data to showcase endothelialization in 14 day
  rabbit iliac models
• Numerous Society updates and recommendations
  given to include ACC, SCAI, AHA, Society of
  Cardiothoracic Surgeons

Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes.
Endeavor is a registered trademark of Medtronic
Inc.
17
FDA confirms the benefits of the TAXUS Stent are
proven, and outweigh any potential risks
FDA Advisory Panel supports the benefits of
Drug-Eluting Stents
Contents of this slide reflect the comments and
observations from the FDA panel conducted in
December 2006 and are for information purposes
18
Glossary

• TAXUS analysis includes TAXUS I (5 yr), II-SR
  cohort I (4 yr), IV (4 yr), V (2 yr) RCTs
• TAXUS I trial TAXUS Stent is the
  Paclitaxel-eluting NIR Stent control is the
  NIR Stent. NIR is a trademark of Medinol Ltd.
  Jerusalem - TAXUS NIR (or NIRx) Stent is an
  investigational device, not for sale in the
  European Economic Area (EEA)
• TAXUS II trial TAXUS Stent is the
  Paclitaxel-eluting NIR Stent control is the
  NIR Stent. NIR is a trademark of Medinol Ltd.
  Jerusalem - TAXUS NIR (or NIRx) Stent is an
  investigational device, not for sale in the
  European Economic Area (EEA)
• TAXUS IV and TAXUS VI trials TAXUS Stent is the
  TAXUS Express Stent control is the Express
  Stent. TAXUS Express Stent is an
  investigational device, not for sale in the
  European Economic Area (EEA)
• TAXUS V trial TAXUS Stent is the TAXUS
  Express² Stent control is the Express² Stent
• TAXUS Express stent is an investigational
  device, not for sale in the European Economic
  Area (EEA
• Paclitaxel-Coated NIR stent NIRx stent is an
  investigational device, not for sale in the
  European Economic Area (EEA) - NIR is a
  registered trademark of Medinol Ltd. Jerusalem
• TAXUS Express² Stent is not approved for use in
  patients with coronary artery reference vessel
  diameters lt 2.25mm or gt 5.0mm
• TAXUS Express² Stent is not approved for use in
  patients with lesions longer than 32mm
• ARTS II is a trial sponsored by JJ, Cordis Corp.
• Syntax is a trial sponsored by Boston Scientific.

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This information is representative of data
presented to the FDA circulatory advisory panel
on December 7th 8th, 2006 by Dr. Donald S.
Baim, Chief Medical and Scientific Officer,
Boston Scientific Corporation. Information
regarding the safety, efficacy, and clinical
performance of the TAXUS stent in patient and
lesion types not included in the TAXUS stent
general indication, such as lesions longer than
32mm, vessels with an RVD lt2.25mm, the use of
multiple overlapping stents, in patients with
diabetes, or for longer than 12 months, are
discussed in this presentation for information
purposes. For specific indications,
contraindications, warnings, and precautions
please see the full TAXUS Express2
Paclitaxel-Eluting Coronary Stent System
DFU. The TAXUS Liberté Stent is not approved
for use in patients with coronary artery
reference vessel diameters lt 2.25mm or gt 4.0mm.
The TAXUS Liberté Stent is not approved for use
in patients with lesions longer than 32mm. TAXUS
Liberte is not approved for sale in the United
States.