CryoCath Technologies Inc. 7 Fr Freezor? Cryoablation Catheter System P020045 FDA Circulatory System Devices Panel Meeting March 6, 2003 Gaithersburg, MD

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CryoCath Technologies Inc.7 Fr Freezor?
Cryoablation Catheter SystemP020045FDA
Circulatory System Devices Panel MeetingMarch 6,
2003 Gaithersburg, MD
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FDA/CDRH/ODE/CEMB PMA Review Team

• James Cheng, Lead Reviewer
• Lesley Ewing, M.D., Clinical and Animal Review
• Lilly Yue, Ph.D., Statistical Review
• Cindy Demian, Biocompatibility Review
• Elaine Mayhall, Sterilization Review
• Kevin Hopson, Bioresearch Monitoring Review

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Sponsor Proposed Indications for Use

• The cryo-ablation of the conducting tissues of
  the heart in the treatment of patients with
  atrioventricular node reentrant tachycardia
  (AVNRT)
• The identification of aberrant conducting tissue
  responsible for supraventricular tachycardia
  using the reversible electrophysiological
  cryomapping of conducting tissue near the AV node
  to minimize risk of AV block

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Cryoablation System Components

• FreezorTM Cardiac CryoAblation Catheter
• CCT.2 CryoConsole
• Umbilicals and Accessories

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FreezorTM Cardiac CryoAblation Catheter

• 7 French single use catheter with 4mm long
  gold-plated metal tip, 3 ECG ring electrodes,
  thermocouple sensor and a flexible, maneuverable
  shaft.
• Refrigerant injection tube, ECG wires, leak
  detection wire, and thermocouple wire are
  contained inside the catheter lumen.
• Catheter handle contains deflection mechanism.

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CCT.2 CryoConsole

• Provides N2O refrigerant delivery recovery.
• Maintains vacuum inside catheter lumen.
• Controls refrigerant pressure and flow rate to
  achieve target temperature ranges.
• Contains device safety systems.
• Monitors integrity of umbilical connections.
• Injection controller uses dedicated hardware and
  has manual override.

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Umbilicals and Accessories

• Coaxial umbilical delivers liquid N2O under
  pressure to the catheter and evacuates N2O gas.
• Electrical umbilical carries catheter
  electrical signals to Auto Connection Box.
• Auto Connection Box connects electrical
  umbilical and ECG cable to console.
• ECG Cable carries catheter ECG signals to
  external monitor.

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Principles of Operation

• Cryogenic temperatures generated only at the
  catheter tip.
• Pre-cooled liquid N2O injected under pressure to
  the catheter tip.
• Liquid N2O expands to a gas inside the tip.
• Phase change is an endothermic reaction.

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Principles of Operation

• CryoAblation catheter tip target temperature
  between 68oC and -75oC maintained for up to 240
  seconds.
• CryoMapping - catheter tip target temperature
  between 25oC and -30oC maintained for 60 seconds.

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FDA Preclinical Review Goals

• Safety ensure that the device has been
  appropriately designed and tested, that potential
  device hazards have been analyzed and mitigated,
  and that safety features have been qualified for
  use.
• Reliability ensure that the device design and
  manufacture provide assurance of consistency with
  performance specifications.

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Preclinical Qualification7F FreezorTM Catheter

• Catheter Testing
• biocompatibility of catheter materials
• reliability of catheter design
• mechanical testing of catheter performance
• electrical testing of catheter performance
• qualification of sterilization procedures

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Preclinical QualificationCCT.2 Console

• Software Qualification assessment of design and
  development methodology, software hazards
  analysis, and verification and validation
  process.
• Hardware Qualification assessment of N2O
  injection and recovery systems design,
  temperature controller performance, device risk
  analysis, and design and performance of device
  safety features.

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System Safety Features

• Primary Hazard Gas Embolism
• Mitigation Features
• Catheter design and qualification (burst and leak
  testing)
• Catheter lumen under continuous vacuum (prevents
  release of refrigerant gas into bloodstream)
• Catheter safety interlock (prevents device
  operation until all catheter connections properly
  configured)

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System Safety Features

• Primary Hazard Gas Embolism
• Mitigation Features
• Redundant blood/fluid detector systems (detects
  blood inside the catheter as a result of a
  catheter leak)
• Injectant flow profile monitoring (detects
  unusual catheter performance)
• Catheter pressure relief valve
• Loss of vacuum detection (disables injection)

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System Safety Features

• Safety Hazard Exsanguination
• Mitigation Features
• Redundant blood/fluid leak detectors along vacuum
  recovery path (disables injection and vacuum)
• Catheter design and reliability validation
  testing (burst and leak testing)

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System Safety Features

• Safety Hazard Freezing Temperatures Along
  Catheter Shaft
• Mitigation Features
• Injectant flow profile monitoring (detects
  unusual catheter performance)
• Catheter qualification testing (demonstrated
  refrigerant tube break did not allow external
  shaft temperatures to approach freezing)

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System Safety Features

• Safety Hazard Software Failure
• Mitigation Features
• Dedicated hardware-based injection controller
  with manual override for stopping injection
  delivery
• Hardware-based watchdog circuitry to monitor for
  software failure

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Preclinical Testing Conclusions

• Preclinical testing performed by the sponsor is
  appropriate and acceptable.
• Specific hazards posed by the device have been
  appropriately analyzed and addressed by the
  sponsors device design and qualification
  testing.
• Overall testing shows that the device is reliable
  for human use.

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Clinical Summary

• Lesley Ewing, M.D.
• FDA, CDRH

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Study purpose

• To study the safety and effectiveness of the
  cryoablation system to treat
• Atrioventricular re-entrant SVT due to accessory
  pathways (AVRT)
• Atrioventricular node re-entry SVT (AVNRT)
• Rapid ventricular response due to atrial
  fibrillation (AF)

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Study Design

• Single arm, non-randomized, multi-center study
  using objective performance criteria (OPC) for
  comparators
• The OPCs were based on the medical literature on
  radiofrequency ablation and designed to be used
  for the entire pooled study population.
• The OPCs have been used in previous ablation
  clinical trials reviewed by the FDA.

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Objective Performance Criteria

• Guidance document issued on July 1, 2002
  Cardiac Ablation Catheters Generic Arrhythmia
  Indications for Use Guidance for Industry
• http//www.fda.gov/cdrh/ode/guidance/1382.html
• Recommendations of this guidance intended for RF
  ablation catheters

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Table 1. Acceptable Endpoint Criteria Based on
Medical Literature
STUDY ENDPOINT TARGET VALUE 95 CONFIDENCE BOUND
Acute Success gt 95 gt 85
Chronic Success gt 90 gt 80
Major Complications lt 2.5 lt 7
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Study Design

• Three patient populations were included in the
  study
• Atrioventricular node re-entry tachycardia
  (AVNRT)
• Atrioventricular reciprocating tachycardia (AVRT)
• Atrial fibrillation (AF)

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Inclusion Criteriapre-electrophysiology study

• Clinical history of SVT or refractory AF with
  rapid ventricular response documented by ECG,
  TTM, or holter
• EF ? 35
• ? 18 years

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Inclusion Criteriapost-electrophysiology study
(EPS)

• EPS documented inducible sustained AVNRT, AVRT,
  or AF with rapid ventricular response

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Exclusion Criteria

• Atrial tachycardia
• Sustained ventricular tachycardia
• Acute MI within 2 months or unstable angina
• Congenital heart defect
• Clinically significant aortic, mitral or
  tricuspid valve disease
• Severe vascular disease
• History of any mitral or tricuspid valve surgery
• NYHA class III or IV
• Any implantable cardiac device except for
  pacemaker in AF patients
• Any cerebral ischemic event in the preceding 3
  months
• Significant coagulation disorder
• Pregnancy
• Hyperthyroidism
• Any previous cardiac ablation procedure

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Primary effectiveness endpointAcute procedural
success

• AVNRT and AVRT absence of spontaneous or
  inducible sustained SVT at end of procedure
• AF absence of AV node conduction at end of the
  procedure

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OPCs
STUDY ENDPOINT Lower or upper 95 CONFIDENCE BOUND
Acute Success gt 85
Chronic Success gt 85
Major Complications lt 7
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Secondary Effectiveness endpoint Long term
success

• AVNRT and AVRT- no recurrence of sustained SVT by
  the time of the 3 month follow-up
• AF absence of AV node conduction at 3 month
  follow-up

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OPCs
STUDY ENDPOINT Lower or upper 95 CONFIDENCE BOUND
Acute Success gt 85
Chronic Success gt 85
Major Complications lt 7
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Safety Endpoint

• The number of major complications following the
  use of the investigational device system should
  have an 95 upper bound of lt 7.

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Definition of major complications

• Major Complication Any adverse event which
  occurs within the first week following use of the
  investigational device and
• is life-threatening or
• results in permanent impairment of a body
  function or permanent damage to a body structure
  or
• necessitates significant intervention, such as
  major surgery, to prevent permanent impairment of
  a body function or permanent damage to a body
  structure or

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Definition of major complications continued

• requires hospitalization or an extended hospital
  stay or
• results in moderate transient impairment of a
  body function or transient damage to a body
  structure or
• requires intervention such as medication or
  cardioversion to prevent permanent impairment of
  a body function or damage to a body structure.

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Study Procedure
Screening and enrollment
Diagnostic eps
Cryomapping at investigators discretion
Cryoablation
Follow-up at 7 days, 1, 3, 6 months
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Study results

• 166 patients were enrolled, 164 received
  cryoablation lesions
• 14 total investigational sites, 11 US and 3
  Canadian

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EPS diagnosis
AVNRT 102/166 61
AVRT 51/166 31
AF 12/166 7
AT 1/166 0.6
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Patient Accountability
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Ablation results
Acute success ()
AVNRT 94/103 (91)
AVRT 34/49 (69)
AF 8/12 (67)
Total 136/164 (83)
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Chronic results
n Lost ? 3 mo Chronic success
AVNRT 94 2 86/94 (91)
AVRT 34 0 30/34 (88)
AF 8 0 6/8 (75)
Total 136 2 122/136 (90)
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Acute major complicationswithin 7 days of
procedure

• 7 patients with 8 acute major complications
• 7/166 patients, 4.2 (1.7, 8.5)
• 3 patients with AVNRT procedure, 4 with AVRT

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Acute major complications
Complication Rhythm RF
1 Prostatitis AVNRT No
2 Pulmonary embolus AVNRT No
3 RA thrombus AT No
4 Introducer sheared AVRT Yes
5 RA thrombus AVRT Yes
6 AMI, stent placed AVRT Yes
7 RV perforation, DVT AVRT no
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Cryomapping

• Mapping performed by using the reversible cryo
  effects on the conduction system
• Use of cryomapping decided per case by
  investigator
• Criteria for effective cryomaps were
  predetermined per tachycardia
• Cryomapping not part of predetermined endpoints
  of the trial

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Cryomapping

• 135 out of 164 patients had cryomap attempts
• 88/135 (65) had effective cryomaps and 47/135
  (35) had only ineffective cryomaps
• Total cryomap attempts was 812 with 161 (20)
  of those effective cryomaps
• negative cryomaps may have helped the
  investigator determine unsuccessful cryoablation
  locations

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Cryomapping safety

• 7 AVNRT patients had not reversible marked on
  data collection forms
• All 7 patients had successful cryoablation
  procedures with no adverse event reported

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Statistical Summary

• Lilly Yue, Ph.D.
• FDA, CDRH
• Division of Biostatistics

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Study Design

• Effectiveness and safety outcomes
• Primary
• Acute procedure success
• Major complication occurrence
• Secondary
• Long-term clinical success at 3-month conditional
  on acute success
• Evaluated for the entire SVT patient population

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Study Design

• Study success criteria
• Acute procedure success
• The lower 95 two-sided confidence
• bound of the acute success rate for all ITT
• patients should be greater than 85.
• ITT Cryoablation catheter activated

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Study Design

• b. Major complication occurrence
• The upper 95 two-sided confidence
• bound of the major complication incidence rate
  for all safety patients should be less than 7.
• Safety patients Cryoablation catheter
  
• inserted

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Study Design

• c. Conditional Long-term clinical success
• The lower 95 two-sided confidence
• bound of the conditional long term success
  rate for all ITT patients should be greater than
  85.

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Study ResultsAcute Success ITT, OPC85
n 164
Success 136
Rate 83 (lt 85)
95 C.I. (76, 88)
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Incidence of Major complicationsOPC 7
n 166
Patients with major complications 7
Incidence Rate 4.2
95 C.I. (1.7, 8.5)
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Conditional Long-term SuccessOPC 85
Protocol-specified Exact C.I.
ITT Excluding L F/U
n 136 136 ?134
Success 122 122
Failure 12 12
Lost to F/ U 2 2 ? 0
Rate 90 122/136 91 122/134
95 C.I. (83, 94) (85, 95)
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Post-hoc Subgroup Analyses

• Subgroup analysis on the ablation safety and
  effectiveness endpoints for the three patient
  subpopulations
• AVNRT AVRT AF
• Subgroup analysis on the impact of effective
  cryomapping on ablation acute success ---
  cryomapping utility

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Post-hoc Claims

• The cryoablation of the conducting tissues of the
  heart in the treatment of patients with
  atrioventricular node reentrant tachycardia
  (AVNRT)
• The identification of aberrant conducting tissue
  responsible for supraventricular tachycardia
  using the reversible electrophysiological
  cryomapping of conducting tissue near the AV node
  to minimize risk of AV block

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Post-hoc Subgroup Analysis

• When should we perform subgroup analysis?
• When the study has succeeded in pre-specified
  overall analysis, may do subgroup analysis
• When the study has failed in pre-specified
  overall analysis, generally do not perform
  subgroup analysis because the risk of false
  positive results increases

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Post-hoc Subgroup Analysis

• Some criteria to judge the validity of subgroup
  analysis
• Prospectively defined hypotheses?
• Biologically plausible subgroup classification?
• Significant treatment effect in overall analysis?
• Significant interaction of treatment with
  subgroup variable?

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Subgroup Analysis on Ablation

• Is there justification to examine the post-hoc
  subgroup analysis?
• Prospectively defined hypotheses? ... NO
• Biologically plausible subgroup classification?
  YES
• Significant treatment effect in overall analysis?
  ... NO
• Significant interaction of treatment with
  subgroup variable? ... ???

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Subgroup Analysis on Ablation

• OPCs developed for entire patient population may
  be wrong for subpopulations, so cant applied to
  subpopulations.
• If the subgroup analysis had been planned in the
  design stage, a multiplicity adjustment, such as
  Bonferroni, for significance level should have
  been performed.

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Subgroup Analysis on Ablation

• Acute Success (OPC85)

AVNRT AVRT AF
Success Rate 91 (94/103) 69 (34/49) 67 (8/12)
95 C.I. (84, 96) (55, 82) (35, 90)
Adjusted C.I. (82, 97) (52, 84) (30, 93)
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Subgroup Analysis on Ablation

• Major Complications (OPC7)

AVNRT AVRT AF
Incidence Rate 2.9 (3/103) 7.8 (4/51) 0 (0/12)
95 C.I. (0.6, 8.3) (2.2, 18.9) (0, 24.5)
Adjusted C.I. (0.4, 9.6) (1.6, 21.5) (0, 32.8)
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Subgroup Analysis on Ablation

• Conditional Long-term Success (OPC85)

AVNRT AVRT AF AVNRT
Success Rate 91 (86/94) 88 (30/34) 75 (6/8) 93 (86/92)
95 C.I. (84, 96) (73, 97) (35, 97) (86, 98)
Adjusted C.I. (82, 97) (69, 98) (28, 98) (85, 98)
Excluding 2 lost to follow-up subjects
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Subgroup Analysis on Ablation

• Results
• Suppose that the OPCs were appropriate for
  the subgroups. For any patient subgroup,
• With or without multiplicity adjustment, the
  study has failed to meet the primary safety and
  effectiveness OPCs
• Conclusion
• None of the three subgroups met the OPCs for
  either primary safety or primary effectiveness.

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Subgroup Analysis on Cryomap

• Patient accountability
• Of 164 patients who got cryoablations, 135
  patients had cryomapping attempts, and 29 did
  not.
• Of the 135 patients who had cryomapping attempts,
  there were 87 patients with effective
  cryomappings and 48 patients with ineffective
  cryomappings
• Effective cryomapping rate 64, (87/135)
• Reversibility rate 92 (80/87)

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Subgroup Analysis on Cryomap

• Ablation acute success

n Ablation Acute Success Ablation Success Rate
Effective 87 82 94
Ineffective 48 31 65
No attempts 29 23 79
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Subgroup Analysis on Cryomap

• Sponsor Grouped ineffective no attempts
• and formed without
  effective
• W/o effective n77, acute success 54,
• 
  failure 23
• Compared effective with without effective
• Concluded that effective was significantly
  better than without effective in ablation acute
  success

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Subgroup Analysis on Cryomap

• Ablation Acute Success

Group Effective W/o effe. p-value
AVNRT (n102) 94 (62/66) 89 (32/36) 0.45
AVRT (n49) 94 (17/18) 55 (17/31) 0.004
AF (n12) 100 (3/3) 56 (5/9) 0.49
Overall 94 (82/87) 70 (54/77) lt0.0001
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Subgroup Analysis on Cryomap

• However,
• The significant result was driven by 49 AVRT
  patients.
• There is no significant difference detected in
  ablation acute success between effective and
  w/o effective patients for AVNRT and AF
  subgroups.

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Subgroup Analysis on Cryomap

• Question
• 1. What is the meaning of the comparison?
• 2. Why grouping Ineffective with no
• attempts?
• 3. Is the subgroup classification, "effective
  
• vs. without effective biologically
• plausible?

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Subgroup Analysis on Cryomap

• If we try to test the impact of effective
  cryomapping on ablation acute success, we could
  compare effective group with ineffective
  group, and use no attempts as a control.
• Ablation acute success 94, 65, 79
• Effective cryomapping rate 64

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Subgroup Analysis on Cryomap

• If we try to test the impact of attempted
  cryomapping on ablation acute success, we could
  compare attempted with no attempts.
• Attempted includes effective and
  ineffective.

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Subgroup Analysis on Cryomap

• Compare attempted with no attempts
• There is no significant difference detected in
  ablation acute success between attempted and
  no attempts groups.
• Ablation Acute Success

Attempted W/o attempts
Succ. Rate 84 (113/135) 79 (23/29)
Exact test p-value 0.59 p-value 0.59
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Subgroup Analysis on Cryomap

• Is there justification to examine the post-hoc
  subgroup analysis?
• Prospectively defined hypothesis? ... NO
• Biologically plausible subgroup classification?
  ... ???
• Significant treatment effect in overall analysis?
  ... NO
• Significant interaction of treatment with
  subgroup variable? ... ???

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Clinical and Statistical Conclusions

• The device did not meet the primary effectiveness
  and safety OPCs for either the overall study
  population or any patient subgroup.
• No patient had unintentional permanent AV node
  block at the end of the procedure or during
  follow-up.

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Clinical and Statistical Conclusions

• There were a low number of recurrences after
  successful cryoablation. Cryoablation lesions
  appear to have a durable effect.

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Clinical and Statistical Conclusions

• The post-hoc assessment of cryomapping
  effectiveness is questionable. There was no
  significant association detected between
  effective cryomapping and ablation acute success
  for the AVNRT subgroup.
• There was no adverse event reported due to
  cryomapping.

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DRAFT FDA Questions for the Circulatory System
Devices Panel
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FDA Draft Panel Questions

• Results of this clinical trial were compared to
  objective performance criteria (OPCs) established
  for the study for both safety and effectiveness.
  The OPCs were determined from the radiofrequency
  ablation medical literature.

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Question 1 Safety

• The safety endpoint was the occurrence of major
  complications, as defined in the study protocol.
  The FDA interprets the definition of major
  complications to include all adverse events
  requiring treatment which occurred within 7 days
  of the procedure. The upper 95 confidence bound
  for the major complication rate was 8.5.

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Question 1 continued

• This exceeded the safety OPC, which specified an
  upper 95 confidence bound of less than 7.
  Please comment on the following
• a. Please discuss whether the results of the
  clinical study provide a reasonable assurance of
  device safety for the intended patient
  population.

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Question 1 continued

• b. Please discuss the applicability of a safety
  OPC for cryoablation which was based on reported
  clinical experience with radiofrequency ablation.

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Question 2 Effectiveness - Ablation

• The device did not meet the effectiveness OPC
  for the overall study population or for any
  patient subgroup. The lower 95 confidence bound
  for acute success for the entire study population
  was 76. The OPC for acute success specified a
  lower 95 confidence bound gt 85.

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Question 2 continued

• a. Please discuss whether the results of the
  clinical study provide a reasonable assurance of
  effectiveness in (a) the overall patient
  population or (b) in any individual patient
  subgroup.
•  
• b. If the clinical trial does not provide enough
  evidence of effectiveness please discuss what
  would be needed.

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Question 3 Effectiveness - Cryomapping

• The submission describes the use of cryomapping
  technology and effectiveness evaluation. Please
  discuss whether the study results show that the
  cryomapping technology is effective for use in
  the intended patient population.

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Question 4 Training/Learning Curve

• Acute success rate varied per institution in
  this study. Acute success rate per institution
  ranged between 0 and 100.
•  
• a. Please discuss the concept of site-based and
  physician-based learning curves.
•  

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Question 4 continued

• b. All new devices inherently involve a learning
  curve in their evaluation. Please discuss
  whether the concept of a learning curve, either
  per site or per physician, may be considered in
  the evaluation of device safety and
  effectiveness.
•  
• c. Please discuss whether and/or what type of
  physician training should be required for this
  device if approved.

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Question 5 Labeling

• Labeling for a new device should indicate which
  patients are appropriate for treatment, should
  identify potential device-related adverse events,
  and should explain how the device should be used
  to optimize its risk/benefit profile. If you
  recommend device approval, please address the
  following
•  

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Question 5 continued

• a. Please discuss whether the proposed warnings,
  precautions, and contraindications are
  acceptable, based on the study results.
•  
• b. Please discuss whether the instructions for
  use adequately describe how the device should be
  used.

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Question 6 Post-Market Study

• If you recommend approval, please discuss
  whether a post-market study should be performed
  to address any issues that are unresolved, but
  not essential to the premarket approval of the
  device.