**SECTION 4**

**FDA SUMMARIES**

**Table of Contents**

1.0 Lead Reviewer & Engineering Summary
[2](#lead-reviewer-engineering-summary)

1.1 PMA Chronology [2](#pma-chronology)

1.2 Summary [2](#summary)

1.3 Device Description [3](#device-description)

1.4 Bench Testing [3](#bench-testing)

1.5 Biocompatibility Testing [4](#biocompatibility-testing)

1.6 Animal Testing [4](#animal-testing)

1.7 Sterility Testing and Package Integrity
[4](#sterility-testing-and-package-integrity)

1.8 Device Failures and Malfunctions - Clinical Use
[4](#device-failures-and-malfunctions---clinical-use)

1.9 Conclusions [5](#conclusions)

4.0 Clinical Summary [6](#clinical-summary)

4.1 Introduction [6](#introduction)

4.2 Pivotal Data Set for Closure of Atrial Septal Defects (Section 5.1)
[7](#pivotal-data-set-for-closure-of-atrial-septal-defects-section-5.1)

4.2.1 Registry Design [7](#registry-design)

4.2.2 Description of Patients [7](#description-of-patients)

4.2.3 Assessment of Patient Outcome [7](#assessment-of-patient-outcome)

4.2.4 24-Hour Evaluation [7](#hour-evaluation)

4.2.5 6-Month Evaluation [8](#month-evaluation)

4.2.6 12-Month Evaluation [8](#month-evaluation-1)

4.2.7 Analysis of Adverse Events [9](#analysis-of-adverse-events)

4.3 Pivotal Data Set for Fenestrated Fontan Closure (Section 5.2)
[9](#pivotal-data-set-for-fenestrated-fontan-closure-section-5.2)

4.3.1 Registry Design [9](#registry-design-1)

4.3.2 Description of Patients [9](#description-of-patients-1)

4.3.3 Assessment of Patient Outcome
[9](#assessment-of-patient-outcome-1)

5.0 Statistical Summary [11](#statistical-summary)

5.1 Introduction [11](#introduction-1)

5.2 Extent of follow-up [11](#extent-of-follow-up)

5.3 Statistical endpoints [11](#statistical-endpoints)

5.4 Possible confounding owing to age and morbidity differences
[12](#possible-confounding-owing-to-age-and-morbidity-differences)

5.5 Poolability of data [13](#poolability-of-data)

5.6 Other issues [13](#other-issues)

5.7 Conclusion [13](#conclusion)

# 1.0 Lead Reviewer & Engineering Summary  {#lead-reviewer-engineering-summary .unnumbered}

**Date:** August 1, 2001

**From:** Donna Buckley, Mechanical Engineer

CDRH/ODE/DCRD/ICDB

**Subject:** Amplatzer® Septal Occluder (ASO) -- Engineering Review

## 1.1 PMA Chronology {#pma-chronology .unnumbered}

September 1, 2000 P000039 received by CDRH/ODE

October 11, 2000 P000039 filed

January 2, 2001 Letter sent to sponsor from FDA requesting additional
information

February 1, 5, 26 Response to FDA's January 2^nd^ letter received

and March 9, 2001

March 19, 2001 FDA requested complete audit of clinical data and
requested additional preclinical and clinical information

April 23, June 28, Response to FDA's March 19, 2001, letter received

July 13, and 19, 2001

September 10, 2001 P000039 Scheduled for Review by Circulatory Systems
Devices Panel

## 1.2 Summary {#summary .unnumbered}

This PMA has been submitted in order to seek marketing approval for the
Amplatzer® Septal Occluder (ASO) for the treatment of: (1) atrial septal
defects (ASD) in secundum position and; (2) closure of the fenestration
following a Fenestrated Fontan (FF) procedure.

The pivotal cohort ("Phase IIB") of patients used to support PMA
approval was generated from patients enrolled in a nonrandomized
concurrently controlled study of ASD patients and a registry of patients
with Fenestrated Fontans.

######## *ASD Indication* {#asd-indication .unnumbered}

To support the ASD indication, the sponsor has submitted data from a
prospective, non-randomized concurrently controlled study comparing
device closure to surgical closure.

Evaluation of composite success included assessment of patients in which
closure was attempted without major complication, surgical
reintervention, embolization, technical failure, or a major shunt (\>
2mm). The 12-month composite success rate was 85.9% (311/362) for device
patients and 94.5% (146/154) for surgical control patients. At 12
months, 1.6% (7/442) of device patients and 5.2% (8/154) of control
patients had major complications. Also, 98.5% (326/331) of device
patients and 100% (149/149) of surgical patients had closure of the
defect (defined as \< 2 mm residual shunt) at 12 months.

The ASD study originally began as a randomized study comparing device
closure to surgical closure (Phase IIA); however, the design was
subsequently changed to a non-randomized design (Phase IIB). Following
numerous reports from the sponsor regarding difficulties in completing a
randomized trial for these patients, FDA held a meeting with the
Circulatory System Devices Panel (October 24, 1997) to discuss trial
design issues for transcatheter septal occlusion devices. During that
meeting, the Panel recommended a non-randomized trial design for ASD
patients. Consequently, the sponsor revised the trial design to a
non-randomized design and those patients included in the non-randomized
trial are the "Phase IIB" patients which comprise the pivotal cohort.

Due to rapid enrollment in the device arm of the non-randomized study
compared to the surgery arm, the number of patients in the device arm
was increased. After all of the surgery patients were enrolled and
preliminary data were submitted for the device patients, the sponsor
requested a Continued Access Study. This study was approved following
review of the preliminary safety data.

######## *Fenestrated Fontan Indication* {#fenestrated-fontan-indication .unnumbered}

To support the Fenestrated Fontan indication, the sponsor has submitted
data from a single arm registry. The results indicate that all patients
had closure of the fenestration (defined as \< 2 mm shunt) at 12 months
without the need for reintervention. Major complications occurred in
4.2% (2/48) of these patients.

These data provide the basis for the analyses presented in this panel
pack. The clinical investigation information is summarized in the
Clinical Summary and Statistical Summary provided by John Stuhlmuller,
M.D., and John Dawson, respectively.

## 1.3 Device Description {#device-description .unnumbered}

The ASO device is a self-expanding, self-centering, repositionable,
double-disk device comprised of nitinol (nickel-titanium alloy) metal
braid and delivered percutaneously. A cylindrical waist that is selected
to correspond to the size of the defect joins the two disks. The device
is intended to be offered in 26 sizes ranging from 4 mm to 38 mm.
Polyester patches have been sewn into the disks and waist in order to
promote a thrombotic response post-placement. Platinum maker bands are
attached at the apex of each disk and a microscrew attachment on the
proximal disk connects the device to the delivery cable. The delivery
cable is made of 304SS and contains a microscrew that is welded to the
distal end for insertion into the microscrew attachment of the ASO
device. A pin vise attached to the proximal end of the delivery cable is
used to unscrew the ASO device from the delivery cable following
deployment. The total Amplatzer system consists of the following
components: (1) dilator, (2) loading device, (3) delivery cable, (4)
plastic pin vise, (5) sizing plate, (6) ASO device, and (7) delivery
sheath (6F to 12F) with side arm and hemostasis valve.

The sponsor has also requested approval for an Exchange System that is
intended to aid in the removal of an Amplatzer device in the event that
the delivery catheter kinks or fails in some way. The Exchange system is
comprised of the same materials and design as the delivery catheter with
the exception that the dilator has a larger inner lumen to allow for
passage over the delivery cables. The Exchange System will be offered in
two sizes (9F and 12F) and will be sold separately. (Note that the
Exchange System was not used in the clinical trial.)

## 1.4 Bench Testing {#bench-testing .unnumbered}

The bench tests conducted using finished, sterilized devices, are
summarized in Table 1.

+--------------------------------+-------------------------------------+
| IMPLANT                        | DELIVERY SYSTEM                     |
+--------------------------------+-------------------------------------+
| -   Pull Test, Laser Welds --  | -   Delivery Sheath Kink Resistance |
|     Marker Bands to Wire Braid |                                     |
|     and Screw Attachment to    | -   Delivery Cable Kink Resistance  |
|     Marker Bands               |                                     |
|                                | -   Pull Tests, Delivery Sheath,    |
| -   Pull Test, Delivery Cable  |     Hub to Tubing                   |
|     -- Delivery Cable Screw    |                                     |
|     and Device End Screw       | -   Pull Test -- Delivery Cable,    |
|                                |     Cable to Cable Screw Weld Joint |
| -   Device Integrity           |                                     |
|                                |                                     |
| -   Cycle Testing              |                                     |
|                                |                                     |
| -   MRI compatibility          |                                     |
|                                |                                     |
| -   Corrosion                  |                                     |
+--------------------------------+-------------------------------------+

**Table 1: Bench Testing**

The testing conducted indicates that the device samples tested performed
within specification. In addition, shelf life testing was conducted to
support a three year shelf life. The conclusion from the fatigue and
corrosion testing is that there is no clear evidence that the device
will fail due to fatigue and there was no gross evidence of corrosion in
the samples tested. Although this is the case and rigorous fatigue
testing was conducted by the sponsor, fatigue failure, perhaps
facilitated by corrosion, is always a concern given that there is no
ideal *in vitro* model to simulate the *in vivo* environment and that
the *in vitro* testing only models a 12-year implant period for a device
that has the potential to be implanted over a lifetime. No wire
fractures have been reported in devices implanted in patients.

## 1.5 Biocompatibility Testing {#biocompatibility-testing .unnumbered}

Biocompatibility tests in accordance with ISO-10993, "Biological
Evaluation of Medical Devices", were conducted on the Implant and the
Delivery Catheters. Test results indicate that the device system is
biocompatible. A summary of the tests conducted is included in Table 2.

  -------------------------- ------------------------ --------------------
  TESTS CONDUCTED            Delivery SySTEM          POLYESTER MATERIAL
                                                      IN IMPLANT

  cytotoxicity                                       

  sensitization                                      

  systemic toxicity                                  

  subchronic toxicity                                 

  intracutaneous reactivity                          

  hemolysis                                          

  chronic toxicity                                   pending\*

  mutagenicity                                        

  muscle implantation                                 pending\*
  -------------------------- ------------------------ --------------------

> \* Test reports for these tests are due by 8/15/01 and will be
> submitted to the FDA.

##### Table 2: Summary of Biocompatibility Testing {#table-2-summary-of-biocompatibility-testing .unnumbered}

## 1.6 Animal Testing {#animal-testing .unnumbered}

Amplatzer ASO devices were placed in 11 swine in which an ASD had been
surgically created. The created ASDs ranged in size from 8 to 16 mm. The
animals were sacrificed at 7 days (N=1), 9 days (N=2), one month (N=5),
three months (N=2) or four months (N=1). There was an acceptable
histological response and tissue in-growth and endothelialization was
complete by 1 to 3 months.

In addition, two swine were sacrificed 14 and 18 months
post-implantation and devices were examined for evidence of corrosion.
Evidence of corrosion or wire fracture was not seen in subsequent
scanning electron microscope studies.

## 1.7 Sterility Testing and Package Integrity {#sterility-testing-and-package-integrity .unnumbered}

The Amplatzer® ASO is sterilized using a 100% ETO cycle that has been
validated to achieve an SAL of 10^-6^ in accordance with ANSI/AAMI/ISO
11135-1994. Sterilization residuals were specified to be below
acceptable maximum limits (25 ppm ethylene glycol, 25 ppm ethylene
chlorohydrin, and 50 ppm ethylene glycol).

## 1.8 Device Failures and Malfunctions - Clinical Use {#device-failures-and-malfunctions---clinical-use .unnumbered}

There were six device procedural failures in 1.41% (6/424) of patients
enrolled in the ASD trial. In three cases, the device embolized and
required surgical removal and in three cases the sheath tip marker band
embolized. In one patient, the marker band was surgically removed. In
the second patient, the marker band was left in the pulmonary artery
branch. In the third patient, the band was removed from the groin site.
In response to these events, the sponsor removed the marker band from
the 9F and 10F delivery sheaths (11/98) and subsequently from all
delivery sheaths (12/99). No other significant device failures or
malfunctions have been noted.

## 1.9 Conclusions {#conclusions .unnumbered}

-   The incidence of device failures and malfunctions during clinical
    use of the Amplatzer was low. The sponsor has attempted to implement
    design, labeling, and training changes to help minimize the
    occurrence of these events.

-   Although no problems with device integrity have been reported, long
    term outcome for the device is unknown.

# 4.0 Clinical Summary  {#clinical-summary .unnumbered}

**Date:** July 2, 2001

**From:** John E. Stuhlmuller, M.D.

CDRH/ODE/DCRD/ICDB

**Subject:** AGA Medical The Amplatzer Septal Occluder System

Indications for Use- (1)Closure of Atrial Septal Defects

\(2\) Closure of Fenestrated Fontan

#  {#section .unnumbered}

## Introduction

Atrial septal defects (ASD) are congenital abnormalities of the atrial
septum characterized by structural deficiency of the atrial septum in
one or more locations. ASDs account for approximately 10% of all
congenital heart disease. Ostium secundum defects are the most frequent
type of ASD. The physiological consequences of an ASD are related to the
size of the left to right shunt and response of the pulmonary vascular
bed to the volume overload. ASD closure is primarily indicated for the
prevention of the pulmonary vascular changes associated with volume
overload.

Table 102 (Appendix III) outlines the different phases of patient
enrollment. Phase I is a single-arm open-label registry. The intent of
this registry was to gain operator experience with the device and
evaluate the initial safety of device use. Devices were placed in 22
patients. Phase IIA was a concurrent randomized study that enrolled 38
patients. Devices were implanted in 32 patients. After initiating the
randomized study, input was obtained from the Circulatory System Devices
Advisory Panel in December, 1997 regarding trial design for septal
occluders. The Panel felt that a non-randomized study design using a
prospective concurrent surgical control arm was satisfactory.

Phase IIB is a multi-center, open-label device registry with a
concurrent surgical control group. Initial sample size estimates
required 130 patients each in the device and surgical arms. FDA agreed
to a combination of retrospective and prospective identification of
patients for the surgical arm. Patient enrollment in the device arm was
completed prior to enrollment of the surgical patients. As a result,
patient cohorts were sequentially enrolled in an extended investigation
registry as part of the continued access provisions based on the
Expanded Access provisions in the Food and Drug Administration
Modernization Act of 1997. The criteria for an extended investigation
include the following:

1.  A justification for the extension;

2.  A summary of the preliminary safety and effectiveness data generated
    under the IDE;

3.  A brief discussion of the risk posed by the device;

4.  The proposed rate of continued enrollment (the number of sites and
    subjects);

5.  The clinical protocol, if different from that used for the
    controlled clinical trial, as well as the proposed objectives for
    the extended study; and

6.  A brief discussion of the sponsor's progress in obtaining marketing
    approval for the device.

A total of 442 patients were enrolled in the Phase II B study. This is
considered the pivotal data set for the evaluation of safety and
effectiveness.

Subsequently, FDA approved a request for additional patient enrollment
under the Continued Access provisions of the Expanded Access provisions
noted above. A total of 465 continued access patients have been enrolled
as of May 2001.

## 4.2 Pivotal Data Set for Closure of Atrial Septal Defects (Section 5.1) {#pivotal-data-set-for-closure-of-atrial-septal-defects-section-5.1 .unnumbered}

### 4.2.1 Registry Design {#registry-design .unnumbered}

The sponsor conducted a multi-center, open-label registry for the device
arm. As noted above, the Phase II B registry is the pivotal device data
set. The control arm consists of patients who underwent surgical
closure. Patients were identified in a retrospective manner after
surgery and prospectively prior to surgery. All completed a prospective
1-year follow-up evaluation.

### 4.2.2 Description of Patients {#description-of-patients .unnumbered}

The patient selection criteria for the device group were intended to
identify patients with an isolated ostium secundum defect with evidence
of volume overload on the right side of the heart. Patient inclusion was
limited initially to defects with diameters of ≤ 26 mm and later to
defects with diameters of ≤ 38 mm based on device sizes. Patients with
pulmonary vascular resistance above 7 Woods units, other types of
cardiac disease such as recent myocardial infarction, and signs of
sepsis were excluded.

The patient selection criteria for the surgical group were similar with
no upper size limit on the defect size or number of defects.

Assessment included clinical evaluation, echocardiography,
electrocardiography, and cardiac catheterization.

Table 9 outlines patient demographic information. The mean age in the
device group was 18 years of age with a range of 0.6 to 82 years of age.
The mean age in the surgical group was 6 years of age with a range of
0.6 to 32 years of age.

Gender distribution was similar between the device and surgical groups
(68% females in the device group and 61% in the surgical group). The
surgical group had larger and multiple defects based on the differences
in the patient selection criteria between the groups. Patient
demographic data in this group was obtained by retrospective chart
review in some cases (37) and prospectively in the rest (117). All
patients required a prospective echocardiogram performed at 12 months
using standardized imaging acquisition.

Overall, both patient groups demonstrated the clinical,
echocardiographic, hemodynamic, and electrocardiographic characteristics
associated with ASDs.

### 4.2.3 Assessment of Patient Outcome {#assessment-of-patient-outcome .unnumbered}

Patient evaluation was required at 24 hours, 6 months and 12 months
after the index procedure.

### 4.2.4 24-Hour Evaluation {#hour-evaluation .unnumbered}

Device placement was attempted in 442 of 459 patients enrolled in the
device arm. Devices were successfully placed in 423 of 442 patients
attempted. Overall, device placement was successful in 92% of patients
enrolled in the study (423 of 459). Statistical analysis is not based on
an intent to treat analysis.

Procedural variables such as procedure and fluoroscopy time are outlined
in Table 16. Mean procedure time in the device arm was 106 minutes with
a range of 33 to 320 minutes. Mean fluoroscopy time in the device arm
was 21 minutes with a range of 3 to 116 minutes.

Table 18 indicates the number of devices used by size. Device size
ranges from 4 mm to 38 mm. Devices in the range from 10 mm to 28 mm
accounted for 89% of devices implanted.

Technical success was defined as successful deployment of the device or
successful completion of surgery. Success rates are reported in Table 19
for patients in which device placement was attempted. Technical failure
was defined as when the device was inserted and recaptured or acute
embolization occurred. Reasons for technical failure were primarily
related to anatomical issues based on defect characteristics such as rim
or size. One acute embolization occurred.

Shunt closure defined as a residual shunt ≤ 2 mm was demonstrated in 413
of 423 (97.6%) patients implanted in the device arm. Shunt closure was
demonstrated in 154 of 154 surgical patients.

Five device embolizations occurred. One occurred upon release from the
delivery system. Three occurred within 24 hours of device placement. One
occurred at 9 days after device placement. Two were removed
percutaneously. Three required surgical removal. No specific clinical
events were noted with the embolizations. Technical issues related to
device sizing and the structural stability of the defect rim contributed
to the occurrence of device embolization. Based on these events, the
investigational plan was modified. A chest x-ray at one week and
providing additional restrictions on patient activity for at least
1-month after device placement were added.

### 4.2.5 6-Month Evaluation {#month-evaluation .unnumbered}

All device patients were scheduled to complete a clinical and imaging
evaluation (echocardiogram and chest x-ray). No specific follow-up was
mandated for surgical patients at this time point.

Follow-up information is provided on 389 of 416 device patients.

Shunt evaluation was completed on 387 device patients. Complete closure
was demonstrated in 341 of 387 patients (88.1%). A shunt was
demonstrated in 46 of 387 patients with a trivial shunt in 10 patients
(2.6%), small shunt in 25 patients (6.5%), moderate shunt in 9 patients
(2.3%), and large shunt in 2 patients (0.5%). Success defined as shunt ≤
2 mm was demonstrated in 376 of 387 patients (97.2%; complete
closure-341, trivial-10, and small-25).

No device fractures were noted.

### 4.2.6 12-Month Evaluation  {#month-evaluation-1 .unnumbered}

All device and surgical patients were scheduled to complete a clinical
and imaging evaluation (echocardiogram and chest x-ray).

Follow-up information is provided on 335 device and 109 surgical
patients.

Shunt evaluation was completed on 331 device patients. Complete closure
was demonstrated in 304 of 331 patients (91.8%). A shunt was
demonstrated in 27 of 331 patients with a trivial shunt in 7 patients
(2.1%), small shunt in 15 patients (4.5%), moderate shunt in 4 patients
(1.2%), and large shunt in 1 patient (0.3%). Success defined as shunt ≤
2 mm was demonstrated in 326 of 331 patients (98.5%; complete
closure-304, trivial-7, and small-15).

All shunts were closed in 94 of 94 surgical patients completing
echocardiographic evaluation.

No device fractures were noted.

### 4.2.7 Analysis of Adverse Events {#analysis-of-adverse-events .unnumbered}

Adverse events were initially categorized as major or minor. The Data
Safety Monitoring Board revised the initial classification to include
major, minor, and observations.

Major adverse events were noted in 7 of 442 (1.6%) Phase IIB device
patients. Major adverse events included the following: cardiac
arrhythmia requiring major treatment in 2 patients (0.5%, pacemaker
placement or long-term drug treatment), device embolization with
surgical removal in 3 patients (0.7%), device embolization with
percutaneous removal in 1 patient (0.2%), device delivery system
malfunction in 1 patient (0.2%, marker band embolization requiring
surgical removal).

Major adverse events were noted in 8 of 154 (5.2%) surgical patients.
Major adverse events included the following: pericardial effusion with
cardiac tamponade in 3 patients (1.9%), pulmonary edema in 1 patient
(0.6%), repeat surgery in 2 patients (1.3%), and wound complications in
2 patients (1.3%).

Minor adverse events were noted in 27 of 442 (6.1%) Phase IIB device
patients. Minor adverse events included the following: allergic
reactions in 2 patients (0.5%), cardiac arrhythmias requiring minor
treatment (required drug treatment) in 15 patients (3.4%), device
embolization requiring percutaneous removal in 1 patient (0.2%),
headaches/possible TIA in 2 patients (0.5%), %), device delivery system
malfunction in 2 patients (0.5%, marker band embolization) and thrombus
formation in 3 patients (0.7%).

Minor adverse events were noted in 29 of 154 (18.8%) surgical patients.
Minor adverse events included the following: cardiac arrhythmias
requiring minor treatment (required drug treatment) in 9 patients
(5.2%), pericardotomy syndrome in 2 patients (1.3%), pericardial
effusion in 6 patients (3.9%) pneumothorax in 3 patients (1.9%), and
transfusion in 2 patients (1.3%).

## 4.3 Pivotal Data Set for Fenestrated Fontan Closure (Section 5.2) {#pivotal-data-set-for-fenestrated-fontan-closure-section-5.2 .unnumbered}

### 4.3.1 Registry Design {#registry-design-1 .unnumbered}

The sponsor conducted a multi-center, open-label registry.

### 4.3.2 Description of Patients {#description-of-patients-1 .unnumbered}

Patients with a fenestrated Fontan baffle with a clinical indication for
closure were eligible for device placement. A minimum distance of 5 mm
between the baffle communication and the atrial free wall and a central
venous pressure less than 15 mm Hg were required.

Device placement was attempted in 48 of 51 patients enrolled in the
registry. Devices were implanted in 46 of 48 patients in which device
implantation was attempted. Device deployment could not be completed in
2 patients.

Table 76 outlines the patient demographic information. The mean age in
the device group was 8 years of age with a range of 1.6 to 45 years of
age. Gender was 60% male.

### 4.3.3 Assessment of Patient Outcome {#assessment-of-patient-outcome-1 .unnumbered}

Patient evaluation was required at 24 hours, 6 months and 12 months
after the index procedure.

Shunt evaluation was completed in 46 patients at 24 hours. Complete
closure was demonstrated in 41 of 46 patients (89%). A shunt was
demonstrated in 6 of 46 patients with a trivial shunt in 3 patients
(6.5%) and a small shunt in 3 patients (6.5%). No moderate or large
shunts were present.

Shunt evaluation was completed in 38 patients at 6 months. Complete
closure was demonstrated in 35 of 38 patients (92%). A trivial shunt was
demonstrated in 3 of 38 patients (8%). No small, moderate or large
shunts were present.

Shunt evaluation was completed in 32 patients at 12 months. Complete
closure was demonstrated in 29 of 32 patients (91%). A shunt was
demonstrated in 3 of 32 patients with a trivial shunt in 1 patient
(3.1%) and a small shunt in 2 patients (6.3%). No moderate or large
shunts were present.

A total of 4 adverse events were noted (major and minor-2 each). The
major adverse events consisted of a hemothorax requiring drainage and a
tricuspid valve tear requiring valve replacement. The minor adverse
events consisted of an occurrence of atrial fibrillation requiring
cardioversion and persistent post-procedure nausea and vomiting
requiring a second night of hospitalization.

# 5.0 Statistical Summary  {#statistical-summary .unnumbered}

**Date:** July 23, 2001

**From:** John Dawson, Mathematical Statistician

CDRH/OSB/Division of Biostatistics

**Subject:** AMPLATZER Septal Defect Occluder, by AGA Medical
Corporation (P000039/A8), July 18, 2001 -- Statistical review

## 5.1 Introduction {#introduction-1 .unnumbered}

All statistical concerns in my October 12, 2000 review memo on P000039
have been addressed: (1) more complete follow-up to 12 months is
reported now, than in the original August 2000 PMA, (2) request for
actuarial estimates of effectiveness and safety endpoints have been
granted, (3) attention has been paid to differences between the device
and surgical control study arms as regards age and morbidity, and (4)
poolability of data across sites has been analyzed.

## 5.2 Extent of follow-up  {#extent-of-follow-up .unnumbered}

The original PMA submission last summer reported that only about half of
the device patients had been followed to 12 months. Now, as of the
cutoff date of May 25, 2001 for this amendment, upwards of
three-quarters of implanted patients are accounted for at 12 months, but
still with some 20% who should have, but did not, have a 12 month visit.

Out of 459 patients enrolled in the AMPLATZER Septal Defect Occluder
device study arm, 17 were not attempted ("Intent to Treat" cases), while
the remaining 442 were attempted. Out of those 442 attempted, 423 were
implanted. Here is the 12-month status of 423 implanted patients (see
pages III-7 & 49):

> 331 had a 12-month visit completed
>
> 68 missed the visit
>
> 12 were lost because of IRB lapse
>
> 4 had the visit but without shunt assessment
>
> 4 were lost-to-follow-up, and
>
> 4 were lost because of non-acute embolizations.

Out of 155 patients enrolled as surgical control patients, all but 1were
attempted. Here is the 12-month status of 154 surgical control patients
(see p. III-7):

> 109 had a 12-month visit completed
>
> 37 missed the visit
>
> 5 were lost because of IRB lapse
>
> 0 had the visit but without shunt assessment
>
> 3 were lost-to-follow-up, and

## 5.3 Statistical endpoints {#statistical-endpoints .unnumbered}

In my statistical review of the PMA, I made said the that endpoints
where patients' had variable exposure times should not be computed as
simple binomial proportions (or percentages). In a teleconference with
the company, they pointed out that there was no variation in exposure
time for the primary effectiveness criterion \-- percentage of patients
at 12 months with successful shunt closure \-- since the denominator
only counted patients with a 12-month visit, so binomial calculations
were appropriate in that case.

***[Primary effectiveness endpoint]{.underline}***: The primary
effectiveness endpoint was residual shunt ≤ 2 mm at the 12-month visit,
with a goal of the device-minus-surgery difference in percent of
patients with effective closure (success) being no less than --8%, as a
lower 1-sided 95% confidence limit. (Protocol, pages 12 and 14) That
target was used in computing the sample size goal of 110 subjects per
study arm.

***Results***: Out of 331 patients with a 12-month visit, 326 had
effective closure (98.5%), compared to 100% closure success in the
surgical control group. (p. III-5) The lower confidence limit on the
device-minus-surgery difference is -5.2%, so they have met the primary
effectiveness criterion. In computing this confidence limit, the rates
are appropriately characterized as binomial variables, since everyone
evaluated at 12 months had the same duration of exposure to the risk of
failure.

***[Primary safety endpoint]{.underline}***: "Acceptable limits" were
defined in the protocol as ≤ 2% deaths and ≤ 10% major complications in
the device group. (Protocol, p.14) I interpret these deterministic goals
as defining the bounds of a device non-inferiority to surgery.

***Results***: There was one death in the device group, which sponsor
considers not device-related deaths; hence, the 2% mortality goal was
met. The goal was also met in the case of major complication, reported
on p. III-9 as 1.6%. Sponsor also undertook to compare that 1.6% with
the 5.2% for surgical controls. Since time-to-complication was variable,
a Cox regression analysis was done, with time-to-complication as the
dependent variable. Study arm was tested as a predictor, for which
sponsor reports a significant p-value: this implies a lower risk of
major complication with the device. Sponsor decided there were too few
events to do covariate-adjustment (i.e. testing age, etc., as
predictors) in the Cox regression analysis. **The small number of events
precluding covariate analysis also precludes a claim of
major-complication superiority**, rather than non-inferiority, for the
device. The Cox results do support a finding of non-inferiority.

## 5.4 Possible confounding owing to age and morbidity differences  {#possible-confounding-owing-to-age-and-morbidity-differences .unnumbered}

I noted in my October review memo that device patients were on average
18 years old, compared to 6 years old in the case of surgical control
patients, and also noted a difference in the device and surgical arms in
percentage of cases with particular morbidities. Sponsor acknowledges
these differences between the study arms (p. III-18) and has now
incorporated age and morbidity as covariates in actuarial modeling, as
will be discussed.

***Effectiveness -- differences due to age and morbidity?***: The
possibility of confounding of differences in effectiveness with
differences in age and morbidity between the study arms was analyzed on
an age- and morbidity-adjusted actuarial basis (p. III-48). The
effectiveness variable in this analysis was the secondary endpoint, "12
Month Composite Success", which was met by all but 15 device and 8
surgical control patients. A composite failure meant "a major
complication, \[consisting of\] surgical reintervention, embolization,
technical failure, or major shunt..." (p. III-6) This combines both
safety and effectiveness considerations, and since the safety issue is
subject to variable exposure time, it needs actuarial statistical
treatment. When computed on an unadjusted actuarial basis, the device
and surgery rates, rounded, are 87% and 93.8%, respectively. (pages
III-53 and 54) This 7% point difference is statistically significant (p
= .043). (p. III-48) But sponsor proceeded to do covariate adjustment,
which they report "raised the p-value to slightly greater than 0.05."
They also add that "None of the covariates contributed significantly to
the Cox regression model," suggesting that the p = .043 is the
definitive result. **While sponsor makes no claim about the 12-month
composite success outcome (p. III-101), it does appear that the lower
rate for device (87% versus 94% for surgery) is at least borderline
significant.**

***Safety***: Sponsor provides an age-adjusted comparison of the study
arms on *all* complications (minor or major), which purports to show
higher incidence in the surgical control arm in all age categories (p.
III-68). The actuarial complication rates were 7.5% and 26.7% for device
and surgery (pages III-71 and 72). Sponsor reports that the inclusion of
covariates did not remove statistical significance. This lends weight to
a claim of device superiority in the case of complications, as long as
no distinction about severity is to be drawn.

## 5.5 Poolability of data  {#poolability-of-data .unnumbered}

Poolability across sites, or other patient subgroups, is a particularly
important issue when the device deployment requires surgical
implantation, which depends on surgical skill. Site-to-site homogeneity
of success rates is key to giving the device user the assurance that the
overall, pooled data accurately reflect what that user can expect.
Poolability across sites, both with respect to site-specific
complications (minor and major), and with respect to the 12 month
composite success, have been addressed by sponsor, using computer
simulation. They conclude the following about site-to-site variation in
12 month rates:

*Secondary safety* variable: Difference among sites is not statistically
significant as regards minor and major complications. (p. III-90)

*Secondary effectiveness variable:* Difference among sites is
significant. (p. III-55) Out of the 20 sites, exactly half had a percent
success above the overall 85.9% for all sites pooled, which combined
accounted for 188, or 54.7% of the total 362 patients. **The practical
significance of the variation in device success rates across sites
should be assessed from a clinical perspective.**

## 5.6 Other issues  {#other-issues .unnumbered}

Sponsor indicates in Table 1 on p. III-5 some 149 surgical control
patients with successful closure at 12 months, but the patient flow
diagram on p. III-7 shows only 109 with a closure assessment, **an
apparent inconsistency.** This does not affect the finding of success in
meeting the --8% target for difference in closure rates.

Since 68+4 = 72 and 37+3 = 40 patients missed the 12-month visit or were
lost to follow-up, in the device and surgical control groups,
respectively, (p. III-7), intent-to-treat (ITT) analysis should be done
on the primary effectiveness variable, 12-month closure, that includes
these cases as assumed treatment failures as of 12 months post-treatment
-- i.e. added to the at-risk denominators but not to the successes in
the numerators. With these changes, the primary success rate for device
is now on the high side of surgical control: 80.9% versus 78.8% and the
lower confidence limit on the difference, -4.1%, still satisfies the
goal of no worse than --8%. **Sponsor should do an ITT analysis of the
12-month composite success data with the patients who were lost to
follow-up or missed the 12-month visit treated as failures after the
date of the last contact.**

I understand there is concern about patients with occluders of sizes
ranging as high as 38 mm. There are too few such patients for any
definitive conclusions. I would point out that of 16 device patients
with occluders of sizes over 30 mm that were evaluated at 12 months,
only 9 were composite success outcomes. (p. III-57) The success rate,
9/16 = 56.2%, has a wide 2-sided 95% confidence interval, 29.9% to
80.2%.

Sponsor did much the same kind of statistical analyses on Fenestrated
Fontans patients as on ASD patients, though based on just 32 patients. I
think this is too small a sub-study to comment on from a statistical
perspective, except to observe that the effectiveness and safety
results, taken at face value, are favorable. (Pages III-103 and 105)

Finally, I need to point out a minor omission: in Table 39, p. III-49:
the 12-month composite success rate for AMPLATZER **was not updated**,
still showing 87.6%. The 85.9% rate is correctly cited on p. III-5 and
III-48.

## 5.7 Conclusion {#conclusion .unnumbered}

Sponsor has shown statistical non-inferiority of AMPLATZER to surgery as
regards the primary safety and effectiveness targets of, respectively,
freedom from major complications and closure success at the 12-month
visit. The closure success rate of 98.5% for AMPLATZER meets the
confidence limit goal for establishing non-inferiority to the 100%
success for the surgical controls. The major complication rate of 1.6%
meets the goal of not exceeding 10%, and the difference between that
1.6% and the 5.2% for the surgical control group was found to be
statistically significant. No deaths were reported in either study
group. These findings are clearly favorable to the company.

On secondary endpoints of particular interest, one is favorable to the
company and one is not: As to the 12-month composite success endpoint,
which is a combined safety and effectiveness measure, the AMPLATZER
success rate appears to be some 7% points lower than for surgical
control (87% versus 93.8%), a difference that is at least borderline
significant -- not favorable. As to minor and major complications
combined, the rates were 7.5% and 26.7% for AMPLATZER and surgery, which
is statistically significant even when covariates are accounted for --
clearly favorable.

##  {#section-1 .unnumbered}

##  {#section-2 .unnumbered}

##  {#section-3 .unnumbered}