**SUMMARY MINUTES**

**MEETING OF THE**

**GENERAL AND PLASTIC SURGERY DEVICES PANEL**

**OPEN SESSION**

**MAY 5, 1997**

**9200 Corporate Boulevard**

**Rockville, MD**

**GENERAL AND PLASTIC SURGERY DEVICES PANEL MEETING**

**Attendees**

May 5, 1997

*Acting Chairperson*

Monica Morrow, M.D.

*Executive Secretary*

Gail Gantt, R.N., M.G.A.

*Voting Members*

Titus Duncan, M.D.

*Temporary Voting Members*

Ricardo Azziz, M.D.

Narayan Deshmukh, M.B.B.S.

Thomas Downs, Ph.D.

Susan Galandiuk, M.D.

Barbara Levy, M.D.

*Industry Representative*

Cindy Domecus, R.A.C.

*Consumer Representative*

Sally Faith Dorfman, M.D.

*FDA Representatives and Presenters*

David B. Berkowitz, V.M.D., Ph.D.

Roxolana Horbowyj, M.D.

Stan Lin, Ph.D.

Stephen Rhodes, M.S.

Celia Witten, M.D., Ph.D.

**OPENING REMARKS:**

Executive Secretary Gail Gantt, R.N., opened the May 5, 1997 General and
Plastic Surgery Devices Panel Meeting by reading the conflict of
interest statement and the list of temporary voting members for this
panel meeting. Ricardo Azziz, M.D., was granted a waiver for
participation. Panel members then introduced themselves.

FDA representatives provided updates on the human tissue regulation
initiative and previous panel recommendations. Celia Witten, M.D.,
Ph.D., described the regulatory framework for cells and tissues as a
tiered approach based on risks to the patients. The framework was
proposed by the Center for Biologics and addresses issues such as
disease prevention, maintaining integrity in the regulatory process,
assessment of safety and efficacy, and communications. According to
Stephen Rhodes, M.S., FDA has approved the Premarket Application for
Dermagraft-TC with the condition that the sponsor conduct post-approval
market approval studies on 200 patients. FDA has received comments on
the proposed reclassification of suction lipoplasty systems. Thus far
comments have been supportive.

**OPEN PUBLIC HEARING:**

No comments were made.

**OPEN COMMITTEE DISCUSSION:**

*Genzyme Corporation Presentation---PMA P960003:*

The sponsor\'s representatives described the device (Sepracoat^TM^);
clinical problems caused by adhesions; clinical trial results, issues,
and analyses; and use of the device in intra-abdominal surgery. The
sponsor representative introduced the Sepracoat™ product as a device
that is a 0.4% solution of sodium hyaluronate that reduces tissue damage
and *de novo* adhesion development when applied during abdomino-pelvic
surgery. After discussing the etiology and incidence of adhesions, the
sponsor representative presented data on its multicenter, random, and
placebo-controlled studies. According to principal investigators,
Sepracoat^TM^ reduced the incidence of available locations with *de
novo* adhesions by 20% and the number of patients with at least one *de
novo* adhesion by 7%. The safety profiles of the placebo and study
groups were found to be nearly identical.

A sponsor representative addressed issues involving choice of endpoints,
the study design and data analysis, treatment and investigator site
interactions, the justification for statistical tests, and the
integration of safety data. His analyses supported the sponsor\'s claims
and were followed by a presentation on the device\'s utility in
abdominopelvic surgery. A sponsor representative concluded that any
adhesion can cause clinical problems and that no completely effective
strategy exists for preventing *de novo* adhesions. The sponsor's
summary concluded that Sepracoat^TM^ has a favorable risk/benefit
profile, and is safe, effective, and useful.

*Panel Discussion:*

In response to a question posed by the panel, the sponsor representative
said that the issue of confining infections had not been looked into.
Sponsor representative responses to further questions included the
following: the majority of *de novo* adhesions (60-70%) result from
laparotomies, 95% of the patients had indirect trauma, and 50% of the
sites in trauma had adhesions not directly related to the trauma.
Methods of standardization of adhesions across the different sites was
discussed. The sponsor representative defined indirect trauma as damage
to tissue that was not directly involved in the surgical procedure.

The sponsor\'s representatives responded to questions posed by Drs.
Azziz and Morrow regarding choice of statistical tests, the
masking/blinding of investigators, intra-observer variability, and the
reproducibility of the scoring system. In their responses to these
questions, the sponsor representatives indicated that the one-tail test
is a more severe test than the two-tailed test, as it requires a higher
level of evidence. The sponsor representatives went on to explain that
neither the surgeon nor the blinded reviewer who was to review the video
tapes of the surgeries knew which patients were given the placebo or the
Sepracoat™ treatment. Finally, the sponsor representatives mentioned
that there had been good correlation between the investigators and the
blinded observers and that this was underlined by the good kappa
correlation score, which was 0.7 between observers. Dr. Barbara Levy
raised concerns about the four surgical sites that were identified as
having statistically significant differences. She was also concerned
with the second-look procedure with enterotomy, the use of
anti-inflammatory agents, and the packing of the bowel during the
surgical procedure. Discussion ensued, concluding with an explanation of
the application procedure. The sponsor\'s representatives stated that
there were no significant allergic reactions, that analyses of variance
were conducted one at a time except for demographic variables, and that
there was no precipitation of antibiotics.

*FDA Presentations:*

FDA presenters summarized preclinical data and provided medical and
statistical reviews. According to lead reviewer David Berkowitz, V.M.D.,
Ph.D., Sepracoat^TM^ coating solution is indicated for reducing the
incidence of newly formed adhesions resulting from incidental tissue
damage. The solution is 0.4% hyaluronic acid in phosphate buffered
saline (PBS) with a viscosity of 300-500 cP. He characterized the
solution as a \"normal constituent of extracellular space.\" He said
that the effectiveness data were based on a rat cecal abrasion model,
and the general toxicology studies using rabbits, guinea pigs, mice, and
rats were negative. Dr. Berkowitz was not concerned with the findings
from the baboon study that showed differences between the treatment and
control groups. While concluding, he noted that the device does not
affect antibiotic use, and it does not inhibit healing.

Medical reviewer Roxolana Horbowyj, M.D., provided a comprehensive
review, describing the peritoneum, adhesion formation and incidence,
device characteristics, and the study design and protocol. Results of
three feasibility studies showed no serious device- related or adverse
events and acceptable handling characteristics.

The sponsor\'s pivotal study design characteristics included the
following: two treatment groups (0.2% and 0.4% sodium hyaluronate) and a
phosphate buffered saline (PBS) control group; 17 investigators at 23
investigational sites; and 362 patients. Results and the sponsor\'s
claims were based on the cohort size of 107 patients (0.4% sodium
hyaluronate) and 108 (PBS). Although the baseline demographic
characteristics were similar between the control and treatment groups,
the control patients had a greater number of pre-treatment lesions (4.5
± 0.5 versus 3.2 ± 0.4). Between the groups, there was a statistically
significant difference in adverse events. Although not device related,
the sodium hyaluronate group suffered more unspecified pain, abdominal
pain, nausea, dizziness, and pharyngitis. Twelve serious adverse events
were also not device related.

Dr. Horbowyj concluded her presentation with a summary of effectiveness
data and a set of questions for the panel to consider. The data show the
incidence of patients with lesions was 95.4% for the PBS group and 88.8%
for sodium hyaluronate group.

In his statistical review, Dr. Stan Lin summarized the sponsor\'s claims
and then reanalyzed the claims of statistical significance of the
efficacy data. He also addressed the adjustment of trial endpoints. Dr.
Lin said that there are significant interaction effects; however, the
trial was not designed to show interactive effects regarding treatment
and site differences. He added that the sponsor did not adequately
address this issue. The difference between the two groups in terms of
reducing *de novo* adhesions is not significant, he concluded.

*Panel Reviews:*

Titus Duncan, M.D., described the etiology, complications,
morphogenesis, and devices used to prevent adhesions. He discussed
issues from a general surgical perspective, and learned that no safety
and efficacy data exist on the use of Sepracoat^TM^ in patients
following pelvic or abdominal irradiation. Dr. Titus concluded that the
sponsor\'s study involved a \"minuscule\" number of patients. He said a
prospective, randomized study would be needed to show clinical benefit
(i.e., that the product reduces obstruction, pelvic pain, or
infertility).

Barbara Levy, M.D., provided a gynecologist\'s perspective. She
questioned if the number of adhesions was an adequate surrogate for
fertility, obstruction, and pain; if all adhesions can be considered
equal; and how a product designed for *de novo* lesions addresses the
30% general complication rate. Dr. Levy also questioned if more
preexisting conditions and pathology can change the characteristics of
the patients---for example, are they more prone to developing adhesions?
Her concluding concern was the relevance of a gynecological model and
study in respect to general surgical procedures. According to Dr. Levy,
the data do not translate claimed benefits to clinical relevance.

*Panel Discussion:*

In response to the panelist\' questions, the sponsor representatives
explained the results of the baboon study (the increase in bleeding
time) and clarified the administration procedure. Panel members then
responded to questions posed by FDA, and Dr. Morrow stated the panel\'s
consensus: (1) Regarding baseline patient characteristics, the panel
remains concerned that the small difference in rate of efficacy may
reflect biological diversity. (2a) The safety of 0.4% sodium hyaluronate
is not a major clinical issue. (2b) There are no significant adverse
risks posed by the use of this product. (3a) The level of reduction in
*de novo* adhesions (88.8% versus 95.4%) is not clinically significant.
Such a small difference cannot clearly demonstrate effectiveness. (3b)
The mean proportion showing reduction in available sites is not
clinically significant.

Panel members discussed the relevance of using a gynecological model,
the use of a higher percentage of sodium hyaluronate, and the time it
takes to administer the product. Dr. Lin restated his rationale for
finding the sponsor\'s clinical results not statistically significant
due to the variance in sites. The sponsor\'s representative responded,
discussion was closed, and the panel was instructed on voting
procedures.

*Vote:*

The panel voted unanimously that PMA P960003 is not approvable due to
lack of evidence of clinical effectiveness. When polled for their
reasons for voting affirmatively on the motion to not approve the PMA,
panel members said only a small difference was found between the two
groups, which was not significant; and the evidence does not support the
claim. To make the application approvable, Dr. Azziz said the sponsor
should use a gynecological model, obtain follow-up data for at least 1
year, use the primary endpoint of incidence, and look at obstruction and
pain. Patients should reflect a more homogeneous mix to avoid intra-site
variance, according to Susan Galandiuk, M.D. Dr. Levy believes that the
sponsor should use fewer sites and standardize the techniques (such as
packing). Lastly, Narayan Deshmukh, M.D., recommends using temporary
colostomy patients.

**ADJOURNMENT:**

The meeting was adjourned at 2:30 p.m.

I certify that I attended this meeting

of the General and Plastic Surgery

Devices Panel on May 5, 1997

and that these minutes accurately

reflect what transpired.

Gail Gantt, RN

Executive Secretary, FDA

I approve the minutes

of this meeting as

recorded in this summary.

Monica Morrow, M.D.

Chairperson

Summary prepared by

Joëlle Lofton

for Elements in Style, Inc.

15065 Joshua Tree Road

North Potomac, MD 20878

Summary Edited by

David Krause on September 25 and October 16, 2000