FDA Summary

1
FDA Summary

• CardioSEAL STARFlex
• Septal Occlusion System with Qwik Load
• NMT Medical
• P000049/S3

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FDA Summary

• FDA Review Team
• Background
• Device Description
• Nonclinical Evaluation
• Clinical Evaluation
• Panel Questions

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FDA Review Team

• ODE - Donna Buckley
• John E. Stuhlmuller, M.D.
• OSB - Gerry Gray, Ph.D.

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Background

• STARFlex has the same design as the CardioSEAL
  device except that a nitinol centering spring has
  been added
• CardioSEAL
• PMA approved (12/01) closure of high risk VSDs
• HDE approved (2/00) closure of PFO in patients
  with recurrent cryptogenic stroke who have failed
  medical therapy

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STARFlex Device Description

• Occluder
• Double umbrella design
• Sizes 23mm, 28mm, and 33mm
• Device size Stretched defect diameter ratio is
  1.7-2.0 1
• Delivery Catheter
• Size 10F
• Qwik Load device - used to collapse and load
  occluder into the delivery catheter

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Nonclinical Evaluation

• In Vitro Testing
• Biocompatibility Testing
• In Vivo (Animal) Testing

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Clinical Evaluation

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Clinical Data Sets

• Pivotal Cohort STARFlex PFO
• Non-pivotal
• CardioSEAL (PFO)
• Clamshell I F/U (PFO)
• STARFlex (non-PFO)

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Pivotal Cohort - PFO

• Patient subset of High-Risk Registry
• Open-label, single arm
• No control group
• Meets criteria for Compassionate Use
• Primarily single-center study

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Pivotal Cohort - PFO

• 49 patients
• Devices placed in 49 of 49 patients attempted

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Patient Outcome Assessment

• Effectiveness
• Primary Complete Defect Closure by
  Echocardiographic Assessment
• Secondary Occurrence of Potential Neurological
  Events after Device Placement
• Safety
• Adverse Events

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PFO - Effectiveness

• Primary Efficacy determined at 6-month F/U
• 44 of 49 implanted patients
• Complete closure reported in 43 of 44 patients
  evaluated
• Technical errors were reported in 9 of 49
  patients
• Secondary Efficacy
• No strokes and 4 transient neurological events
  were reported

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PFO - Safety

• Assessment at 1, 6, 12, and 24 months
• Characterization of adverse events
• Device related
• arm fractures
• Implantation related
• Catheterization related

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PFO - Safety

• Serious or moderately serious adverse events in
  13 of 49 patients
• Device-Related - 7
• Implantation-Related - 1
• Catheterization-Related - 5
• Arm fractures in 7 of 49 devices

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Panel Questions
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Question 1
1a. Please discuss the use of Procedural
Success as the primary efficacy outcome measure
for assessment of clinical benefit. 1b.
Please discuss the use of the occurrence of
potential embolic neurological events after
device placement as a secondary efficacy outcome
measure for assessment of clinical benefit.
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Question 2
2a. Please discuss the use of Serious and
Moderately Serious Adverse Events (that were
definitely, probably or possibly related to the
device, implantation or catheterization
procedure) as the primary safety outcome measure
for assessment of clinical benefit versus risk.
2b. Please discuss whether the
echocardiographic evaluation and clinical
evaluation (definitions for occurrence of
neurological events) allow adequate assessment of
device-related clinical events.
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Question 2 (cont)
2c. Please discuss whether adequate information
has been provided to allow assessment of the risk
of recurrent cryptogenic stroke versus risk of
device-related neurological event. 2d. Please
discuss whether adequate information has been
provided to characterize the appropriate
post-device placement antiplatelet regimen
(duration and single versus combination therapy)
or anticoagulation regimen (duration and target
INR).
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Question 3
3. Please comment on the lack of a pre-specified
control group, pre-specified outcome measures,
and pre-specified sample size.
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Question 4a and 4b
4a. Please clarify if additional analyses on the
current data set could be performed to
provide adequate information to
support safety and effectiveness. 4b. Please
clarify if the collection of additional data
using the current patient selection criteria
and outcome measures would be adequate
to support safety and effectiveness.
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Question 4c
4c. Alternatively, if you believe that a new
trial is required, please address the
following clinical trial design
questions i. Given our current
understanding of the causal
relationship of the presence of PFO and stroke
(presumed paradoxical embolism), please
discuss whether a randomized trial is
necessary to evaluate safety and
effectiveness. If so, 1. Can a randomized trial
be completed at this time? 2. What is an
appropriate control group?
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Question 4c (cont)
ii. Please discuss whether adequate trials can
be designed with historical controls or
objective performance criteria. iii. Based on
the type of study design proposed, please
address the following issues 1. Please
characterize the appropriate patient population
for study enrollment. 2. Please discuss the
appropriate primary and s secondary outcome
measures for evaluation of effectiveness
and safety. As part of this discussion,
please comment on the use of clinical versus
surrogate endpoints.
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Question 4c (cont)
3. Please discuss the appropriate duration of
patient follow-up. 4. Please comment on what
would be a clinically relevant sample size.
5. Please discuss the criteria for a successful
trial. 6. Please comment on whether adjunctive
antithrombotic medication regimens should be
left to the operator or prospectively outlined
in the protocol.
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Question 5
5. Please discuss any improvements that could
be made to the training program.
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Question 6
6a. Please comment on the INDICATIONS FOR USE
section as to whether it identifies the
appropriate patient populations for treatment
with this device.
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Question 6 (cont)

• 6b. Please comment on the CONTRAINDICATIONS
  section as to whether there are conditions
  under which the device should not be used
  because the risk of use clearly outweighs any
  possible benefit.

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Question 6 (cont)

• 6c. Please comment on the WARNING/PRECAUTIONS
  section as to whether it adequately describes how
  the device should be used to maximize benefits
  and minimize adverse events.

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Question 6 (cont)
6d. Please comment on the OPERATORS
INSTRUCTIONS as to whether it adequately
describes how the device should be used to
maximize benefits and minimize adverse events.
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Question 6 (cont)
6e. Please comment on the remainder of the
device labeling as to whether it adequately
describe how the device should be used to
maximize benefits and minimize adverse events.
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Question 7
7. Based on the clinical data provided in the
Panel Package, do you believe that additional
follow-up data or post market studies are
necessary to evaluate the chronic effects of the
implantation of the STARFlex device. If so, how
long should patients be followed and what
endpoints and adverse events should be measured?