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**SUMMARY MINUTES**

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**MEETING OF THE CIRCULATORY SYSTEM DEVICES ADVISORY PANEL**

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**OPEN SESSION**

 

 

 

 

**FEBRUARY 5, 2001**

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Gaithersburg Marriott

9751 Washingtonian Boulevard

Gaithersburg, MD

**Circulatory System Devices Advisory Panel Meeting**

**February 5, 2001**

**Attendees**

**Acting Chairperson**

Cynthia M. Tracy, M.D.

Georgetown University Hospital

**Executive Secretary**

Megan Moynahan

Food and Drug Administration

**Voting Members**

Salim Aziz, M.D.

University of Colorado

Michael D. Crittenden, M.D.

Harvard University

Warren K. Laskey, M.D.

University of Maryland School of Medicine

**Consultants**

Michael Domanksi, M.D.

NHLBI

Mitchell W. Krucoff, M.D.

Duke University Medical Center

George W. Vetrovec, M.D.

Medical College of Virginia

Francis J. Klocke, M.D.

Northwestern University Medical School

David L. DeMets, Ph.D.

University of Wisconsin, Madison

**Consumer Representative**

Robert A. Dacey

**Industry Representative**

Gary Jarvis

St. Jude Medical

**Food and Drug Administration**

James E. Dillard III

Stuart M. Portnoy, M.D.

Chris M. Sloan

Suzanne Kaiser

Gary Kamer

Paul L. Chandeysson, M.D.

Bram Zuckerman, M.D.

John E. Stuhlmuller, M.D.

 

 

**CALL TO ORDER**

Acting Chairperson Cynthia Tracy, M.D., called the meeting to order at
8:09 a.m. and asked the panel members to introduce themselves. Executive
Secretary Megan Moynahan read the conflict-of-interest statement, noting
that because of his status as a special government employee, panel
consultant Mitchell Krucoff, M.D., could not participate in the morning
panel deliberations. Dr. Tracy, Warren Laskey, M.D., George Vetrovec,
M.D., and David DeMets, Ph.D., had received conflict-of-interest waivers
and could participate fully in all discussions. Dr. Krucoff could
participate fully in all afternoon discussions.

James Dillard, director of the Division of Cardiovascular and
Respiratory Devices (DCRD), announced that Dr. Laskey and Salim Aziz,
M.D., had been appointed to serve 4-year terms and that Dr. Tracy had
been appointed chair of the panel for the duration of her term.

**OPEN PUBLIC HEARING**

No comments were made.

**SPONSOR PRESENTATION: PERCUSURGE/MEDTRONIC**

Dennis Wahr, M.D., St. Joseph Mercy Hospital, presented an overview of
the PercuSurge GuardWire System as used in the Saphenous Vein Graft
Angioplasty Free of Emboli Randomized (SAFER) Trial. He described why it
is important to develop successful surgical intervention techniques for
deteriorating saphenous vein grafts (SVG's) and explained how the
PercuSurge GuardWire System works.

Donald S. Baim, M.D., Brigham & Women's Hospital, provided more details
on the SAFER Trial design and outcome. He noted that an important
component of the PercuSurge system is that it enables aspiration of
embolic particles dislodged during angioplasty, thereby reducing the
rate of major adverse clinical events (MACE). He explained that the
inclusion criteria for the SAFER trial had to be expanded early in the
study because enrollment was too slow; this expansion was done in
consultation with FDA's Data Safety and Monitoring Board. Ultimately,
the study enrolled 142 patients under the original criteria (the RCT\*-1
group) and 659 patients under the expanded criteria (the RCT-2 group),
for a total of 801 patients. SAFER Trial results indicated that patients
who received angioplasty with the PercuSurge device had a significantly
lower rate of MACE than did patients who had the procedure with the
control device. Dr. Baim presented additional study data supporting the
efficacy of the PercuSurge device.

Richard Kuntz, M.D., Brigham and Women's Hospital, presented information
on the statistical techniques used to analyze the results of the SAFER
Trial. Expanding the inclusion criteria created some analytical
challenges, and Dr. Kuntz described ways in which the sample of 801 was
divided into separate cohorts and analyzed. Dr. Kuntz concluded that the
RCT-2 group best represents patients with vein graft disease and
therefore provides the best data set for estimating the MACE differences
between the treatment and control groups.

Dr. Wahr then presented data on the actual use of the PercuSurge system.
He described how physicians were trained to use the device, how device
malfunction was defined, and what the malfunction rates were. He noted
that improvements made to the PercuSurge device part way through the
study reduced the malfunction rate.

**FDA PRESENTATION**

Suzanne Kaiser, biomedical engineer, Interventional Cardiology Devices
Branch, Office of Device Evaluation, and lead reviewer for the
PercuSurge system, summarized the nonclinical tests conducted on the
PercuSurge system and discussed the results of the clinical
investigation of the device. She said that the animal, bench, and
biocompatibility testing demonstrate the integrity and functionality of
the device for its intended use, although issues related to the shelf
life of the device and its packaging remain to be addressed with the
sponsor. She noted that the incidence of device failures and
malfunctions during clinical use of the system appeared to be high and
that FDA is continuing to work with the sponsor to address the issue.

Paul Chandeysson, M.D., medical officer, Peripheral Vascular Devices
Branch, DCRD, provided an overview of the SAFER trial design and
summarized the results. He suggested some possible reasons for the
apparent difference in the RCT-1 and RCT-2 groups and noted that
differences in lesion characteristics between the two groups may have
affected outcomes.

**OPEN COMMITTEE DISCUSSION**

Dr. Laskey noted that to truly examine efficacy, it is important to look
at procedural risk as well as 30-day and 1-year MACE rates. He added
that it would have been helpful to have data on graft ages and
characteristics of the lesions in the SAFER study participants. Finally,
Dr. Laskey said that the data from the RCT-2 group \"carries the day.\"
He asked for clarification on the use of MACE as an endpoint; on whether
the presence of calcification is actually a marker for some other
characteristic; on the relationship between device malfunction and MACE
rates; and on the study's use of creatine kinase (CK) as a surrogate
marker. Drs. Kuntz and Baim answered his questions to his satisfaction.

Michael Crittenden, M.D., asked Dr. Wahr whether anyone had looked at
operator-specific outcomes; Dr. Wahr responded that although the data
had not been specifically tracked, anecdotal evidence is that it takes
operators three or four cases to become comfortable with the device. Dr.
Crittenden asked whether any graft-specific data were available, and Dr.
Kuntz replied that most grafts were more than 6 or 7 years old. Finally,
Dr. Crittenden asked what would be considered a high rate of device
malfunction, and Mr. Dillard replied that the FDA considers a rate of
more than 30 percent to be \"not small.\" Deborah Hinman, MSc.,
PercuSurge, pointed out that after the device was modified, failure
rates declined.

Michael Domanksi, M.D., noted that for CK levels to be effective as a
surrogate marker, they would have to have some relationship to
mortality; however, the trial was not powered to look at mortality. Dr.
Kuntz elaborated on the role of CK levels as a marker in the study and
described the use of left ventricle dysfunction as an indicator of
mortality risk.

Francis Klocke, M.D., pointed out that the MACE rates in the roll-in
portion of the study suggest the influence of a learning curve, and he
questioned how enthusiastically the device should be recommended for
lower risk patients. Dr. Bain agreed that it is not surprising that the
rate of complications was higher for people just learning to use the
device. Dr. Wahr pointed out that at least two-thirds of the roll-ins
were high-risk patients.

Dr. DeMets asked the sponsor questions about the statistical methodology
of the SAFER Trial analysis, which Dr. Kuntz attempted to answer. Dr.
DeMets stated that he rejected the notion of two trials (i.e., RCT-1 and
RCT-2) and instead saw the study as one trial with subgroups.

Panel members asked the sponsor to clarify matters concerning the
training process for the device, the use of the device in animal models,
the use of CK rather than troponin as an indicator, and whether the
device could be used on sequential vein grafts. Dr. Wahr responded to
their questions to their satisfaction. Panelists asked questions
concerning the second indication for use listed in the draft labeling,
but Ms. Hinman explained that it was based on predicates in the
literature and was not related to the SAFER Trial. The panel then turned
to the FDA's questions.

**Question 1. Please discuss whether there are any substantial
differences in the lesions treated in RCT-1 and RCT-2 that could affect
the poolability of the data.**

The panel generally agreed that data on the lesions in the two groups
could be pooled

**Question 2. A substantial difference in 30-day MACE rates was noted in
the control arm of the SAFER Trial after inclusion/exclusion criteria
were modified. . . . Please comment on this difference in control
results. Are there any other methods that should be used to assess
interventional risk in a diseased SVG graft?**

The panel concurred that the age of the graft is an important
consideration in assessing risk. Dr. Laskey added that the clinical
characteristics of the lesions are important and that one would need to
look at more than CK cutoffs.

**Question 3. Considering both the planned a priori and realized post
hoc interim looks at these data, do you have any recommendations
regarding the following questions:**

-   **Please discuss the Type I error values that should be associated
    with each planned or realized look. These values must assure an
    overall study Type I error of 0.05. Their values may not only impact
    the results of hypotheses tests but may also change the widths of
    the reported confidence intervals. These changes could influence the
    evaluation process and the labeling.**

-   **Please discuss whether the 142 patients enrolled prior to the
    change in the inclusion criteria should be included in the primary
    analysis. If not, which patient cohort should be the primary
    analysis cohort?**

Dr. DeMets referenced his earlier remarks and reiterated that he would
focus on the entire study sample of 801 patients; the RCT-1 group is
basically an interesting subgroup. He thought it made sense to adjust
the P value, but not the confidence interval. The panel concurred with
his comments.

**Question 4. Please discuss the clinical importance of the device
failure and malfunction**

**events in the evaluation of the safety and effectiveness of the
GuardWire System.**

The panel concurred that the high device failure rate was cause for
concern and that it was reasonable to ask for additional modifications
to the device.

**Question 5. Based on the data submitted by the applicant please
discuss whether the benefits of the distal protection device in this
patient population outweigh the risks associated with the use of this
device.**

The panel concurred that the benefits of the device outweigh the risks.

**Question 6. One aspect of the premarket evaluation of a new product is
the review of its labeling. The labeling must indicate which patients
are appropriate for treatment, identify the products potential adverse
events, and explain how the product should be used to maximize benefits
and minimize adverse effects. Please address the following questions
regarding the product labeling (Section 2):**

**6a. Based on the data from RCT-1 and RCT-2 as discussed in question 2,
do you recommend that the PercuSurge device be labeled for use in all
SVG lesions? Please comment on the INDICATIONS FOR USE section (page 2)
as to whether it identifies the appropriate patient population for
treatment with the device.**

Dr. Tracy suggested that the data would support using the device in all
types of SVG's until a better way to identify lesions is developed. Dr.
Laskey noted that the device is not suitable for use with ostial lesions
and that the warning should be repeated in the labeling.

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

The panel suggested no contraindications.

**6c. Please comment on the WARNINGS and PRECAUTIONS sections as to
whether it identifies all potential hazards regarding device use.**

Dr. Tracy noted that the sponsor had pointed out that elevated CK levels
were linked with increased mortality; she suggested that MI could be
listed as an adverse event. The panel concurred that information on the
need for special training in the use of the device should be included.

**6d. Please discuss whether any improvements could be made to the
labeling to help minimize the occurrence of device failures and
malfunctions as discussed under question 4.**

Dr. Tracy noted that this issue had been covered in the panel's earlier
discussion.

**6e. Please comment on the remainder of the device labeling as to
whether it adequately describes how the device should be used to
maximize benefits and minimize adverse events.**

The panel had no additional comments.

**6f. Do you have any other recommendations regarding the labeling of
the device?**

The panel had no additional recommendations in response to the question.

**Question 7a. Please discuss any improvements that could be made to the
training program to help minimize the occurrence of device failures and
malfunctions as discussed under question 4.**

Dr. Tracy suggested that sequencing training as the sponsor had
described earlier---training a primary operator, who in turn trains
those assisting him or her---was a rational approach. The panel
concurred. Dr. Baim noted that the company's policy is to not sell the
device to any facility unless it has an operator who has used the device
in at least five cases.

**Question 7b. Please identify any other important elements that should
be contained in a physicians training program for this device.**

The panel had no additional comments.

**OPEN DISCUSSION: CLINICAL STUDY DESIGN ISSUES FOR DISTAL PROTECTION
DEVICES USED IN SVG DISEASE**

Dr. Kuntz discussed some of the problems with conventional RCT
methodology, including the length of time required to obtain results and
the ethical dilemmas that arise when early results indicate significant
benefit from the experimental device. He described a new statistical
methodology that enabled conventional RCT's to be converted to
equivalence trials should early results warrant it. Committee members
expressed interest in his idea.

Dr. Baim waived his presentation.

Dr. Wahr presented information on the differences between occlusion
technology and filter technology. He noted that occlusion technology
enabled a greater quantity of particles to be removed than did filter
technology.

Michael Gibson, M.D., UCSF Medical Center, talked about the use of GP
IIb/IIIa inhibitors in angioplasty. He described a study that compared
Tirofiban and Abciximab, which found that the latter drug produced
superior outcomes, using death and MI as endpoints. Dr. Gibson suggested
that drugs that have similar mechanisms of action and which appear to be
equivalent may actually differ when tested \"head to head.\" He
suggested that additional trials involving GP IIb/IIIa inhibitors in
angioplasty might be warranted.

Ms. Hinman discussed the considerations that should be examined to
protect the public health in the study of distal protection devices in
SVG's. She concluded that in light of the treatment effect of the SAFER
trial, the technical differences between the GuardWire and other
designs, the new nature of vein graft intervention, the regulatory
history of approval of interventional cardiology devices, and the lack
of obvious public health need, other distal protection devices should be
randomized against PercuSurge's GuardWire or standard medical practice.
Panel members asked questions concerning the nature of possible trials
and PercuSurge's involvement in those trials. Dr. Krucoff urged that
PercuSurge allow data from the SAFER trial to be used as a historic
control for an equivalency-style registry.

Julie Broderick, Kensey Nash Corporation, noted that technology is
changing rapidly, presenting challenges for those conducting clinical
trials. She requested that the panel give serious consideration to the
hybrid study design described by Dr. Kuntz that morning.

Gregg Stone, M.D., Lenox Hill Heart and Vascular Institute, provided
background information on pathways to regulatory approval for distal
protection devices in treating SVG's and discussed advantages and
disadvantages of RCT's and registry approaches. He offered three
conclusions: (1) After the PercuSurge device becomes clinically
available, it will no longer be ethically justifiable to complete
superiority trials involving distal filter devices. (2) Registry
approval pathways will be undermined, unacceptable so, by a control
selection bias, confounders, and the lack of an adequate equivalency
database. (3) A noninferiority trial comparing a new device with the
GuardWire, randomized with approximately 800 patients (the size of the
SAFER trial) and using a 510k approval pathway (in case the study did
show equivalence) to expedite its arrival on the U.S. market after panel
review, would provide important efficacy data. The process would be
safer to the public, less burdensome, and fairer to the industry.

Jim Gustafson, vice president, Quality Systems and Regulatory/Clinical
Affairs, Possis Medical, gave a presentation on clinical trials for
distal protection devices in SVG's. He described the AngioJet
Thrombectomy Catheter System, a device that is undergoing IDE clinical
trial for ischemic stroke. He described the preliminary results of the
trial, noting that one of the benefits of the AngioJet is that it
actively dislodges and removes potentially embolic material prior to
treatment; other types of distal protection devices generally evacuate
the debris following treatment. He summarized by saying that any FDA
guidance for clinical trials of distal protection devices should
accommodate, among other considerations, patient selection, endpoint,
and control implications of device design and treatment strategy to
ensure that the results properly serve and inform both practitioners and
the public.

Jerry Mezger, CEO and president, EndiCor Medical, described the X-SIZER
Catheter System, a mechanical thrombectomy device for native vessels and
SVG\'s to prevent distal embolization. He described the preliminary
results of clinical trials with the device and highlighted some study
enrollment issues, including participation at key sites and biased
lesion selection in randomized patients. He concluded by saying that
\"in the post-PercuSurge era, historical MACE rates may be the only
valid standard for comparison\" and asked the panel to take the issues
he raised into account in evaluating EndiCor's ongoing RCT.

William O'Neil, M.D., director of cardiology, William Beaumont Hospital,
reiterated other speakers' concerns about the feasibility of and ethical
issues involving RCT's for approving distal protection devices. He urged
the panel to consider registries or noninferiority trials. He added that
although the device in the SAFER trial could be improved upon, the
question remains of how to get promising devices on the market in a
timely fashion. It is critical for the panel to consider the mode of
failure in considering failure rates.

Stuart Kim, attorney, McKenna & Cuneo, Washington, DC, asked that the
panel discuss, if possible, what unique measures (if any) should be
included in the clinical study design of a proximal protection device
for SVG disease. The panel chose not to discuss Mr. Kim's query because
it did not fit with the agenda, time was limited, and the question was
not clear.

**FDA PRESENTATION**

Bram Zuckerman, M.D., F.A.C.C., medical officer, DCRD, presented
information on trial design issues associated with evaluation of distal
protection devices in diseased SVG's. He pointed out that although
percutaneous coronary treatment of SVG disease is often a preferred
treatment strategy, a wide range of procedure success and complication
rates has been reported for such procedures. Part of the variability can
be explained (e.g., graft age, lesion length), but other factors are
unknown. He said that development of safe and effective distal
protection devices is an important research area in interventional
cardiology; key issues in evaluation of those devices in diseased SVG's
involve control groups, study endpoints, and study protocol. He noted
that MACE is a composite endpoint.

**PANEL DISCUSSION**

The panel moved directly to consideration of the FDA's questions.

**Question 1a: Given our current understanding of vein graft disease,
please discuss the need for a randomized trial design when evaluating a
new distal protection device for SVG use. When is a randomized trial
necessary to ensure comparison to an appropriate control group?**

The panel had mixed views on this question. Dr. Crittenden stated that
an RCT was always necessary, whereas Dr. Domanksi suggested that a
general rule was not possible. He added that for new concepts and
designs, one cannot always use historical data. Dr. Tracy raised the
issue of how to define the appropriate control group. Dr. Krucoff said
that the answer to the question was a \"life cycle\" issue and would
vary.

**Question 1b: Please discuss whether adequate trials can be designed
with historical controls or objective performance criteria for
assessment of this technology.**

Dr. Dillard commented that the panel had answered the question in its
discussion of Question 1a.

**Question 1c: If a randomized trial is warranted, please discuss
whether the control arm should incorporate use of an approved distal
protection device. If so, please discuss use of an equivalence
hypotheses, rather than a superiority hypothesis, for this study.**

The panel concurred that the appropriate control is the standard of
practice. Dr. DeMets suggested that the question of equivalence versus
superiority hypotheses was not an either/or proposition and was not
necessarily a good way of looking at the issue. The panel raised issues
of determining and obtaining the appropriate sample size for controlled
trials. Members also noted that centers' differing standards of care
affect studies. Dr. Domanksi suggested that new devices should be tested
by people using the best standard of care. Dr. Laskey pointed out that
the more an operator uses a device, the better the results are; studying
actual device use is a moving target.

**Question 2: Please discuss use of the 30-day MACE rate as the primary
endpoint in a SVG distal protection device trial. Please discuss whether
use of this composite endpoint captures important clinical events.
Please discuss whether an in-hospital or 14-day MACE rate would be
acceptable as a primary endpoint. Please discuss any alternatives to
MACE that would be important to consider.**

Dr. Tracy said that the lack of definition of high-risk vessels had to
be addressed. Dr. Krucoff indicated that he thought the 30-day MACE rate
was appropriate and that he would be concerned about using a 14-day
rate. Dr. Laskey asked whether the FDA was concerned about safety or
effectiveness and emphasized that MACE is a safety endpoint. He asked
whether other endpoints---such as those beyond 30 days---should be
included. Mr. Dillard acknowledged that the area was a complex one and
that MACE has been treated as a catchall endpoint. Dr. Tracy noted that
the device design changed part way through the SAFER study and that one
endpoint component would be device failure.

**Question 3: Please discuss what secondary endpoints should be
emphasized in a SVG distal protection device trial. For example, should
a pathological description of the type and amount of debris removed by
the device be included?**

Panelists had a variety of suggestions, including the different
components of MACE; device-related elements, such as ease of use, device
failure, and secondary interventions due to the device; and effect on
patient quality of life (QOL). Panelists were in general agreement that
although it is difficult to capture, QOL is an important measure. Dr.
Laskey suggested that QOL could be a postmarket measure.

**Question 4: Please comment on appropriate entry criteria for a SVG
trial that is intended to evaluate a new distal protection device.
Please discuss any specific patient populations that should be excluded
or studied separately.**

The panel concurred that any SVG disease constitutes appropriate entry
criteria. Dr. Vetrovec suggested that clot volume and relative flow at
the outset could be a factor.

**Question 5: Please comment on use of adjunctive antithrombotic
medications. Please discuss, for example, whether glycoprotein IIb/IIIa
drug use should be left to operator discretion or be prospectively
outlined in the protocol.**

The panel concurred that it was not appropriate to outline the use of GP
IIb/IIIa at this point. Dr. Krucoff suggested that it was another
heterogeneous standard-of-care issue and that it would be better for the
FDA to focus on randomization and other issues. Dr. Laskey suggested
that diabetics should be studied separately because they have different
outcomes.

**ADJOURNMENT**

Dr. Tracy adjourned the open public hearing at 3:22 p.m.

> I certify that I attended this meeting of the Circulatory System
> Devices Advisory Panel Meeting on February 5, 2001, and that these
> minutes accurately reflect what transpired.
>
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> Megan Moynahan
>
> Executive Secretary
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>  

I approve the minutes of this meeting

As recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Cynthia M. Tracy, M.D.

Chairperson

 

 

Summary prepared by Caroline G. Polk

Polk Editorial Services

1112 Lamont St., NW

Washington, DC 20010

202-265-8271