# Presentation: 333450

## Slide 1

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

## 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

## 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**

## Cryoablation System Components

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

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## Preclinical Qualification7F 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

## Preclinical QualificationCCT.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.

## 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)

## 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)

## 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)

## 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)

## 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

## 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 sponsor’s device design and qualification testing.
- Overall testing shows that the device is reliable for human use.

## Slide 20

## Lesley Ewing, M.D.
FDA, CDRH

- Lesley Ewing, M.D.
- FDA, CDRH

## 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)

## 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.

## 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](http://www.fda.gov/cdrh/ode/guidance/1382.html)_
**Recommendations of this guidance intended for RF ablation catheters**

## Table 1. Acceptable Endpoint Criteria 

**Based on Medical Literature**

| STUDY ENDPOINT | TARGET VALUE | 95 % CONFIDENCE BOUND |
| --- | --- | --- |
| Acute Success | > 95 % | >= 85 % |
| Chronic Success | > 90 % | >= 80 % |
| Major Complications | < 2.5 % | <= 7 % |

## Study Design

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

## Inclusion Criteriapre-electrophysiology study

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

## Inclusion Criteriapost-electrophysiology study (EPS)

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

## 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**

## Primary effectiveness endpointAcute 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

## OPCs

| STUDY ENDPOINT |  Lower or upper 
95 % CONFIDENCE BOUND |
| --- | --- |
| Acute Success | > 85 % |
| Chronic Success | > 85 %* |
| Major Complications | <   7 % |

## 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

## OPCs

| STUDY ENDPOINT | Lower or upper
95 % CONFIDENCE BOUND |
| --- | --- |
| Acute Success | > 85 % |
| Chronic Success | > 85 %* |
| Major Complications | <   7 % |

##  Safety Endpoint

- The number of major complications  following the use of the investigational device system should have an 95% upper bound of < 7%.

## 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

## 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.

## Study Procedure

- Diagnostic eps

- Cryoablation

- Screening and enrollment

- Follow-up at 7 days, 1, 3, 6 months

- Cryomapping at investigators discretion

## Study results

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

## EPS diagnosis

| AVNRT | 102/166 | 61% |
| --- | --- | --- |
| AVRT | 51/166 | 31% |
| AF | 12/166 | 7% |
| AT | 1/166 | 0.6% |

## Patient Accountability

## Ablation results

|  | Acute success (%) |
| --- | --- |
| AVNRT | 94/103 (91) |
| AVRT | 34/49  (69) |
| AF | 8/12 (67) |
| Total | 136/164 (83) |

## 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%) |

## Acute major complicationswithin 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**

## 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 |

## 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

## 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

## 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

## Slide 48

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

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

## 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

## 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**

## 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**

## 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%*.

## Study ResultsAcute Success ITT, OPC:85%

|    n |     164 |
| --- | --- |
| # Success  |     136 |
|  Rate  |      83% (< 85%) |
| 95% C.I. |   (76%, 88%) |

## Incidence of Major complicationsOPC: 7%

|    n |        166 |
| --- | --- |
| # Patients with major complications |         
          7 |
| Incidence Rate |       4.2% |
| 95% C.I. |    (1.7%, 8.5%) |

## Conditional Long-term SuccessOPC: 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%) |

## 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”

## 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

## 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

## 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?

## 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? ... ???

## Subgroup Analysis on Ablation

- OPCs developed for entire patient population may be wrong for subpopulations, so can’t 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.

## Subgroup Analysis on Ablation

- Acute Success (OPC:**85**%)

|  | 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%)  |

## Subgroup Analysis on Ablation

- Major Complications (OPC:**7**%)

|  | 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%) |

## Subgroup Analysis on Ablation

- Conditional Long-term Success (OPC:85%)

|  | 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**

## 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.

## 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)

## 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% |

## Subgroup Analysis on Cryomap

- Sponsor:  Grouped “ineffective” & “no attempts”
-                      and formed  “without effective”
- “W/o effective”: n=77, acute success: 54,
-                                                 failure: 23
- Compared “effective”  with “without effective”
- Concluded  that “effective” was significantly better than “without effective” in ablation acute success

## Subgroup Analysis on Cryomap

- Ablation Acute Success

| Group | “Effective” | “W/o effe.” |  p-value |
| --- | --- | --- | --- |
| AVNRT
(n=102) | 94% 
(62/66) | 89% 
(32/36) |   0.45 |
| AVRT
(n=49) | 94% 
(17/18) | 55% 
(17/31) |  0.004 |
| AF
(n=12) | 100%
(3/3) | 56%
(5/9) |   0.49 |
| Overall | 94% (82/87) | 70% (54/77) | <0.0001 |

## 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.

## 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?**

## 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%

## 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”.

## 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 |  |

## 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? ... ???

## Slide 77

## 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**.

## Clinical and Statistical Conclusions

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

## 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.**

## Slide 81

## DRAFT FDA Questions for the Circulatory System Devices Panel

## 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.

## 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%.  **

## 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.**

## Question 1: continued

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

## 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 > 85%.

## 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.

## 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.

## 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.

## 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.

## 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:

## 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.

**Notes:**
biocompatibility of catheter materials
reliability of catheter design (thermal cycling, torsional and tensile stress, burst, fatigue, connector)
mechanical testing of catheter performance  (steering, stiffness, compression, radiopacity)
electrical testing of catheter performance (noise, mapping, stimulation)
qualification of sterilization procedures.

## 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.