**SUMMARY MINUTES**

**OF THE**

**MEDICAL DEVICES DISPUTE RESOLUTION PANEL**

**OPEN SESSION**

**September 6, 2001**

**Salons E, F and G**

**Gaithersburg Marriott**

**9751 Washingtonian Blvd.**

**Gaithersburg, Maryland**

> **Medical Devices Dispute Resolution Panel**

**September 6, 2001**

**Panel Participants**

Scott D. Ramsey, MD, PhD

Acting Panel Chair

Mark D. Carlson, MD, MA

Voting Member

Ralph B. D'Agostino, PhD

Temporary Voting Member

Gerald J. Shirk, MD

Temporary Voting Member

Kim L. Thornton, MD

Temporary Voting Member

Hector Hugo Gonzalez, RN, PhD

Consumer Representative

Judy Gordon, DVM

Industry Representative

# FDA Participants

Les Weinstein, Esq

CDRH Ombudsman and

Executive Secretary, Medical Devices Dispute Resolution Panel

David Kraus, PhD

Office of Device Evaluation

Roxolana Horbowyj, MD

Office of Device Evaluation

Richard Kotz

Office of Surveillance and Biometrics

# OPEN SESSION

**Acting Panel Chair Scott Ramsey, MD, PhD**, called the session to
order at 8:08 AM by reading the summary of the scientific issues in
dispute. He noted on November 15, 2000 the Office of Device Evaluation
(ODE) in FDA's Center for Devices and Radiologic Health sent Lifecore
Biomedical a "not approvable" letter for its Premarket Approval
Application (PMA) P990015, Intergel Adhesion Prevention Solution.

In the process of determining the safety and effectiveness of this
device, today's panel would have to determine 1) whether there is a
clinically significant difference between Intergel Solution and the
control and 2) whether the benefits outweigh the potential risks (in
particular, the risk of infection) of this device.

**Dr. Ramsey** asked the panel members to introduce themselves, which
they did.

**Panel Executive Secretary Les Weinstein** read for the record
temporary voting status for Drs. D'Agostino, Shirk and Thornton. He then
read the conflict of interest statement and noted that a waiver was
granted to Dr. D'Agostino. The agency had taken into consideration other
matters regarding Drs. Carlson and D'Agostino and had allowed their full
participation in today's panel meeting.

# OPEN PUBLIC HEARING

**Michael Kettel, MD**, a Principal Investigator of Intergel stated that
this product reduced adhesions at the surgical site and also at distant
sites from the surgical area.

**Lena Holmdahl, MD, PhD**, a medical researcher of adhesion formation
and treatment of adhesions in Goteborg, Sweden noted that due to various
reasons, clinical outcome studies cannot be completed in the pre-market
approval phase of this device.

**Russell Malinak, MD**, an emeritus professor of Obstetrics and
Gynecology at Baylor College of Medicine, had participated in the
Intergel Pivotal Study and found the product both safe and effective. He
added that the study was well designed, chose the right outcome (the
adhesions), and focused on the appropriate site (the adnexa).

**Dr. Melvin Thornton**, Assistant Professor of Women's Reproductive
Care at Columbia University, was an Intergel Study participant who, not
only thought that the device was safe and effective, but also easy to
use.

**Panel Executive Secretary Les Weinstein** read letters supporting the
approval of Intergel from the American Society of Reproductive Medicine
and from the Pacific Gynecology Specialist Group in Seattle, Washington.

# Sponsor Presentations

**PREMARKET APPROVAL APPLICATION P990015/A10 \[11\] LIFECORE**
**BIOMEDICAL, INC.'s INTERGEL Adhesion Prevention Solution**

# 

**Dr. Karen Becker** summarized the sponsor's position on scientific
issues by detailing the significance of intraperitoneal adhesions and
presenting the sequence of the approval process of this device. Since
the General and Plastic Surgery Devices Panel meeting of January 12,
2000, an animal study was completed that demonstrated no increased
incidence of infection, and the intended use of Intergel has changed
from general surgery to gynecologic pelvic surgery.

**Dr. Douglas Johns** reviewed the results of the Pivotal Clinical
Trial. In this blinded, multi-center study the safety of this device was
comparable to the control (lactated Ringer's solution). Efficacy was
established since both the number of adhesions and the treatment
failures were reduced.

Beginning the clinical presentation, **Dr. Luigi Mastroianni** stated
that eight medical experts independently reviewed the data of this
trial. Their consensus opinion stated that, in addition to Intergel
being safe and effective, the study design, execution, and analysis
yielded valid data.

**Dr. Alan DeCherney** reported the methodology used in this trial was
valid and conformed with that of the American Fertility Society. He
asserted that the risk of moderate to severe adnexal adhesions decreased
five-fold with the use of Intergel compared with the control solution.

**Dr. Sebastian Faro** addressed the safety issue by concluding that
Intergel was as safe as the control. The animal study revealed no
post-operative infections.

**Dr. Ted Colton** introduced the six statistical issues studied by a
group of experts retained by Lifecore. The consensus opinion of this
statistical group concluded that the clinical trial was well designed
and the analyses were scientifically sound.

**Dr. Steven Piantadosi** thought the Pivotal Study featured a
well-designed trial with good adherence to the protocol. The data from
Europe and the US can be pooled because both locations employed a common
protocol and produced a common treatment effect.

**Dr. Ted Colton** stated the power calculations for the Pilot Study and
the Pivotal Study were valid and correct as calculated.

**Dr. Donald Rubin** noted that the FDA treated the Intention-to-Treat
(ITT) patients or the 6% who did not have a second look procedure as
worst-case outcomes. While this technique unfavorably skews the outcome
of the trial, Dr. Rubin's blinded analysis results in a favorable
outcome which is similar to that of the patients who had second-look
procedures.

The panel members questioned the sponsor about the stability of the
analysis, the low drop out rate in the Pivotal Trial, and how the
protocol would by rewritten retrospectively.

# FDA Presentations

After mentioning the original indications for the device and the new
indications in the present PMA submission, **Dr. David Kraus**
introduced the FDA presenters.

**Dr. Roxolana Horbowyj** reviewed the pathophysiology of adhesions and
the American Fertility Society (AFS) scoring system, together with the
modified and retrospective scoring systems employed in the Intergel
study. Reviewing both the Pilot and Pivotal Studies, she noted in the
Pivotal Study, the European and American cohorts are not comparable with
respect to race, incidence of baseline number of adhesions, or type of
surgical procedure. Since the occurrence of moderate to severe
post-operative adhesions is rare in this patient population, comparing
the resulting small numbers may be clinically insignificant. In some
instances, the difference in outcome between Intergel and the control
was even less than one adhesion.

**Richard Kotz** restated the original study protocol and reviewed 1)
the primary endpoint, modified AFS (mAFS) scores, 2) secondary endpoint,
number of adhesions, and 3) additional endpoints, subsets of adhesions
(reformed, de novo, and surgical site adhesions.) The sponsor's proposed
protocol and analysis plan was to include 200 US subjects and 80
European subjects and was to assign worst scores to subjects lost to
follow-up, Intent-to treat (ITT) group. The sponsor stipulated three
conditions: 1) baseline demographic pretreatment variables (including
adhesion scores) should be similar between the device and control, 2) no
significant interactions should occur between the continents with
respect to treatment efficacy, and 3) the second look scores should be
similar between the device and control.

Because the baseline values are statistically different and an
interaction does occur between the change from the baselines, the data
should not be pooled between the continents. The analysis of the data
from US ITT outcome of mAFS scores and number of adhesions reveals no
significant difference between Intergel and control. From this analysis,
the secondary endpoint data also becomes questionable. The number of
patients with moderate to severe adhesions forms too small a group to be
statistically meaningful.

The panel questioned the FDA presenters about the appropriateness of
pooling the data between continents and the FDA's concentration on the
ITT group when three cohorts were outlined in the protocol.

# Sponsor Rebuttal

**Dr. Karen Becker** stated that the sponsor's Pivotal Trial provided
three evaluable cohorts. The worst case scenario analysis was required
in the original IDE, but was to be replaced with actual data after
completion of the Pivotal Trial. In a deficiency letter the FDA
requested standard AFS scores for all trial patients.

**Dr. Piantadosi** pointed out the baseline differences are
inconsequential. The adhesiolysis patients behave differently from all
other patients, but behave similarly with their subgroup on the other
continent. When the adhesiolysis variable is taken into account, the
data became poolable. A subset analysis has not been employed in the
sponsor's statistical review.

**Dr. Rubin** noted that the worst case scenario for the ITT patients
was unscientific and incorrectly prejudiced the outcome results.

**Dr. DeCherney** explained that the AFS scores were calculated
retrospectively from the modified AFS data that were gathered
prospectively. Furthermore, Intergel does not incite infection in
patients or in animals.

The meeting was recessed at 12:11 p.m. and was reconvened at 1:00 p.m.

# PANEL DISCUSSION

**Acting Panel Chair Dr. Scott Ramsey** reread the questions for the
panel. The first concern was **whether the statistically significant
differences between Intergel and control can be considered to be
clinically significant**.

**Dr. D'Agostino** wanted to know whether the original panel heard
either the AFS derived data or the earlier modified AFS data. The
sponsor stated the original panel heard the results from both data sets.

**Dr. Shirk** found the Pivotal Trial a test with many parameters, no
control on the surgery procedures used at adhesiolysis, and 80% of the
patients with no adhesions at baseline.

**Dr. Gordon** stated that the shift scores, which the sponsor did not
have a chance to present, could address some of the issues in terms of
surgical factors.

**Dr. Piantadosi** answered that randomization permitted reduction of
bias in a large study.

**Dr. Rubin** added that "noisy" data (as in this study) contributed to
smaller estimated effects.

**Dr. D'Agostino** feared that these shifting end-points were a search
for a good outcome.

**Dr. Piantadosi** explained that consistency was tested by means of a
sensitivity analysis. In this study, several assumptions or imputations
were made and the outcomes were compared.

**Dr. Shirk** wanted to know if the protocol for the Pivotal Study was a
statistically fair model and why.

**Dr. Piantadosi** concluded that the Pilot Study was irrelevant to
understanding the results of the Pivotal Trial that was a randomized
study.

**Dr. Horbowyj** remarked that the number of patients who had a positive
result was very small.

**Dr. Carlson** asked if the percentage difference in adhesions was
significant, since the number of adhesions in the Pivotal Study was so
low.

**Dr. Piantadosi** replied that the protocol was a theoretical
construct.

**Dr. Richard Chiacchierini**, Vice President, Statistics, C.L. McIntosh
and Associates, stated that each patient should be taken as an
independent data point with the same opportunity to generate adhesions.

**Dr. Scott Ramsey** noted that the problem before the panel is relative
risk reduction versus absolute risk reduction.

**Dr. DeCherney** stated that the relative risk reduction was five-fold
in the Pivotal Trial.

**Dr. Gere diZerega** cited that since the expected failure rate in this
gynecological population is 13%, the 2% failure rate of Intergel is a
great improvement.

**Dr. Ramsey** posed the second question, **whether the benefits of the
product** **outweigh the risks, including any risk of infection**.

**Dr. Clark** asked if the infection rate in the Intergel group and the
control group was clinically significant.

**Dr. Mastroianni** replied that the incidence of infection in this
group of patients was very low.

**Dr. Shirk** asked what were the indications for use.

**Dr. Mastroianni** answered the indications included lysis of
adhesions, attempted correction of infertility, and removal of ovarian
cysts.

# SECOND OPEN PUBLIC HEARING

**Ms. Bess Weatherman**, Vice Chair, National Venture Capital
Association -- Medical Group, warned that unexpected decisions by the
regulatory agencies add risk to the association's investments. Today's
decision by the FDA may influence the development of many future medical
devices.

**Dr. Mark Marder**, Chairman of Obstetrics at Franklin Square Hospital,
Baltimore, Maryland, came as a patient advocate to speak in favor of
Intergel.

**Dr. Melvin Thornton** showed a short video documenting moderate to
severe adhesions.

The meeting was recessed from 2:19 PM. until 2:31 PM.

**Augusta Sisler**, a patient, explained how it feels to have adhesions.

# PANEL DELIBERATIONS AND VOTE

**Executive Secretary Les Weinstein** read the panel voting options as
Approval, Approvable with Conditions and Not Approvable.

A motion was made and seconded to recommend the device for Approval. A
brief discussion ensued, followed by a unanimous 4 to 0 vote in favor of
approval of the device. The voting members stated the reasons for their
vote for approval. After Dr. Gonzalez and Dr. Gordon made closing
comments, **Acting Panel Chair Scott Ramsey** concluded that in the
future he thinks this panel will be used as a last resort for dispute
resolution. He also commented that the panel's vote is merely a
recommendation to the CDRH Director, but he hoped that the strength of
the consensus will be taken very seriously in the ultimate decision. He
then thanked the panel, FDA, and the sponsors before adjourning the
meeting at 2:54 p.m.

I certify that I attended the Open Session of the Medical Device Dispute
Resolution Panel Meeting on September 6, 2001, and that this summary
accurately reflects what transpired.

S/s

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

Les Weinstein, Esq.

I approve the minutes of this meeting as recorded in this summary.

S/s

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

Scott Ramsey, MD, PhD

Acting Panel Chair

Summary minutes prepared by

Lynne Blei

8916 Burdette Road

Bethesda, Md. 20817

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