**SUMMARY MINUTES**

**OF THE**

**GASTROENTEROLOGY AND UROLOGY DEVICES**

**ADVISORY PANEL MEETING**

**OPEN SESSION**

**October 19, 2000**

**Best Western Washington Gateway Hotel**

**Grand Ballroom**

**1251 West Montgomery Avenue**

**Rockville, Maryland**

**Gastroenterology and Urology Devices**

**Advisory Panel**

**October 19, 2000**

**Panel Participants**

Anthony N. Kalloo, M.D.

Panel Chair

Gastroenterologist

The Johns Hopkins University

Craig F. Donatucci, M.D.

Voting Member

Urologist

Duke University Medical Center

Joseph H. Steinbach, Ph.D.

Voting Member

Biomathematician

V.A. Medical Center

Diane K. Newman, RNC

Consumer Representative

DKN Medical Associates

Michael S. Banik

Industry Representative

Boston Scientific

Robert R. DiLoreto, M.D.

Temporary Voting Member

Urologist

Michigan Institute of Urology

Richard Gorman, M.D.

Temporary Voting Member

Pediatrician

Private Practice

Martin Kaefer, M.D.

Temporary Voting Member

Pediatric Urologist

Indiana University/Riley Children's Hospital

Naida B. Kalloo, M.D.

Temporary Voting Member

Pediatric Urologist

**FDA Participants**

Jeffrey W. Cooper, D.V.M.

Executive Secretary, Gastroenterology and Urology Devices Panel

Daniel Schultz, M.D.

Acting Director

Division of Reproductive, Abdominal, and Radiological Devices

Elisa Harvey, D.V.M., Ph.D.

Acting Chief

Urology and Lithotripsy Devices Branch

Dave Segerson

Associate Director

Division of Reproductive, Abdominal, and Radiological Devices

John Baxley

Biomedical Engineer

Hector Herrera, M.D., M.P.H.

Medical Officer and Urologist

Judy Chen

Statistician

# Sponsor Participants

Dr. Claes Mörlin (Q-Med)

Dr. Göran Läckgren (Clinical Investigator)

Dr. Nicola Capozza (Clinical Investigator)

Dr. Bengt Agerup (Q-Med)

Dr. Hege Bothner Wik (Q-Med)

Mark Yacura (Buchanan Ingersoll)

Ted Sullivan (Buchanan Ingersoll)

**OPEN SESSION**

**Panel Chair Anthony N. Kalloo, M.D.,** called the session to order at
9:31 a.m., noting that the voting members present constituted a quorum
and asking the panel members to introduce themselves and give their
areas of expertise.

**Panel Executive Secretary Jeffrey W. Cooper, D.V.M.,** read
appointments to temporary voting status for Drs. Gorman, Kaefer, and
Naida Kalloo, noting that Dr. Gorman was a consultant to the Center for
Drug Evaluation and Research. Dr. Cooper also read the conflict of
interest statement, noting that Ms. Diane Newman had declared a past
interest in the sponsoring firm on an unrelated issue and her full
participation was permitted. He listed tentative future panel meeting
dates as March 9, June 29, September 13, and December 7, 2001.

**OPEN PUBLIC HEARING**

There were no requests to address the panel from the audience.

OPEN COMMITTEE DISCUSSION\--PREMARKET APPROVAL APPLICATION P000029 FOR
Q-MED'S DEFLUX INJECTABLE GEL

**Sponsor Presentation**

**Dr. Claes Mörlin** introduced the sponsor team. **Dr. Bengt Agerup**
explained the composition of the Deflux device, which is an injectable
gel composed of dextranomer particles and a hyaluronic acid carrier. Dr.
Agerup listed the uses of dextran in various fields, in particular as a
plasma volume expander, and the mechanism of action, with special focus
on particle size and its relationship to the possibility of particle
migration.

**Dr. Hege Bothner Wik** explained the conclusions drawn from
preclinical data. Animal studies showed no adverse reactions, and the
injected material remained stable. Histopathologic observations showed
that the Deflux reflected a good tissue tolerance with an expected
foreign body reaction at injection site and no significant side effects.
Studies showed no translocation of implant material to other tissues
within two years, no cytotoxicity, no delayed contact hypersensitivity
in guinea pigs, and no mutagenicity. It produced acceptable induced
reactions after implantation in rabbit muscle and intracutaneously.
Hemolysis was less than 5 %, and no change in DNA profile was observed
in animal studies.

**Dr. Göran Läckgren** listed treatment options for vesicoureteral
reflux (VUR), which include prophylactic antibiotics, surgery, and
endoscopic injection of bulking agents, which is not approved in the
United States for grades I-III VUR. He listed the advantages of
endoscopic treatment, noting that it provides a cost-effective
alternative to antibiotic prophylaxis that can be done as an outpatient
procedure. He reviewed technical aspects of the Deflux injection and
showed a video of the procedure.

Dr. Läckgren also reviewed the Deflux 1 study, a nonrandomized safety
and efficacy study in Sweden of 50 children older than one year of age
with VUR grades III-IV. He listed inclusion and exclusion criteria and
explained the study design and demographic profile. Safety data results
included adverse event rates, clinical laboratory findings, ultrasound
findings, and rates of urinary tract infections (UTIs), none of which
raised serious safety concerns. Using the protocol definitions, efficacy
results at 12 months showed a 64% success rate (no reflux), an 11%
positive rate (improvement), and a 25% failure rate per ureter.

**Dr. Nicola Capozza** presented data from the Deflux II nonrandomized
study in Italy of 120 children with VUR grades II-IV. He outlined study
objectives, inclusion and exclusion criteria, study design, and
demographic characteristics. Dr. Capozza discussed safety in terms of
adverse events, clinical laboratory findings, glomerular filtration, and
ultrasound findings, none of which raised concerns. Efficacy results at
12 months post-treatment, according to protocol definitions and analyzed
per ureter, showed a success rate of 68%, a positive rate (improvement
to grade I) of 8%, and a failure rate of 24%.

**Dr. Capozza** presented data from the Deflux III study, which was a
randomized study in Italy comparing the Deflux implant to long-term
prophylactic treatment with antibiotics by means of micturition urethro
cystography or MUCG results at one-year post-treatment. He explained the
study design, inclusion and exclusion criteria, and demographics, noting
that there were 99 patients screened, with 38 not included. Of the
remaining 61, 21 received long-term prophylaxis and 40 received the
implant, with 31 of the latter finishing the protocol. Safety results
showed one adverse event and nine episodes of UTI during the study
period. Efficacy results showed a cure rate of 69% of Deflux patients
with VUR grade greater than or equal to II, compared to a cure rate of
33% of those on antibiotic prophylaxis.

Questions to the sponsors from the panel members included clarification
of the protocol, length of follow-up, expected length of treatment
effect, animal study data on displacement and longevity of the implant,
histopathologic studies, and possible differentiation of retreatment
rates by grade of pretreatment VUR. Several panel members had questions
regarding the procedures for blinded reading of ultrasounds, the
learning curve for physicians injecting the gel, and the recommended use
of prophylactic antibiotics during treatment.

# FDA Presentation

**John Baxley, biomedical engineer in the Urology and Lithotripsy
Devices Branch,** introduced the FDA presentation and the FDA review
team. He noted that the PMA was granted expedited review because the
device met regulatory criteria of treating an irreversibly debilitating
condition and having the potential to offer a clear, clinically
meaningful advantage over alternatives.

Mr. Baxley described the device and its intended use and the mechanism
of action, which increases tissue bulk to produce coaptation of the
ureteral orifice and thus blockage of refluxing urine. Chemical testing
verified sufficiently low levels of impurities; and biocompatibility
testing for cytotoxicity, hemolysis, sensitization, intracutaneous
toxicity, and mutagenicity produced no concerns. Biocompatibility
testing included 90-day muscle implantation in rabbits, two-year bladder
submucosa implantation in rabbits and dogs, and a migration study in
rabbits. The tests showed that particle migration was unlikely and
carcinogenicity and reproductive toxicity testing was not warranted.
Other preclinical tests on injectability time and peak force, as well as
stability, produced satisfactory results.

Mr. Baxley noted that the clinical studies were performed in Uppsala,
Sweden, and Rome, Italy, and he summarized the conditions under which
the FDA accepts foreign data. Studies 1 and 2 were done with no control
population and were designed as safety studies only. Renal damage was
not thoroughly assessed, and there were some missing data. Study 3 was a
randomized, controlled trial designed to assess safety and effectiveness
that assessed renal damage and followed patients closely. General FDA
concerns with Study 3 involved the fact that it was a single site study;
there were also questions on whether patient demographics and baseline
characteristics were sufficiently diverse and whether the range of
treatment methods was sufficient. In addition, the FDA raised the
possibility of investigator bias, given that the evaluation of reflux
grades was not blinded.

**Hector H. Herrera, M.D., M.P.H., medical officer and urologist in the
Urology and Lithotripsy Devices Branch,** gave the FDA clinical review,
noting that this was the first bulking agent to request clearance for
this intended use. He explained the international classification system
for grading reflux and also the mechanism of action and injection method
for Deflux. Success for the device studies was defined as no reflux at
12 months; failure as persistent reflux.

Dr. Herrera described patient randomization in Study 3, the primary
study. This single-center study randomized 61 patients into a control
arm of 21 patients treated with antibiotics only and an implant arm of
39 patients treated with Deflux. Both arms were highly similar at
baseline; the majority of all patients were Caucasian. Dr. Herrera
summarized that effectiveness results at 12 months showed a 33% patient
success rate for control and a 69% patient success rate for Deflux in
Study 3.

Dr. Herrera also gave overviews of Study 1 in Sweden, which showed a 56%
patient success rate in 43 patients and of Study 2 in Italy, which
showed a 61% patient success rate in 107 patients. Retreatment consisted
of a single reinjection offered to Deflux patients with persisting
reflux at three months, with retreatment rates varying from 16% to 27%
in the studies. Baseline grade of VUR appeared to have a strong impact
upon the success of Deflux treatment, ranging from 90% effectiveness for
Grade II to 33% for Grade IV in Study 3.

Dr. Herrera outlined safety measures in Study 3, which consisted of
scintigraphy, serum chemistries, ultrasound, and IVP for kidney and
bladder function and kidney/ureter status (no deterioration in either
arm), UTIs (9 in Deflux arm, 0 in control), and reporting of adverse
events (0 in Deflux arm, 1 in control). In Studies 1 and 2,
scintigraphy, serum chemistries, and IVP either were not assessed
post-treatment or were predominantly missing. These studies found no
increase in ureteral dilatation either study. Study 1 reported no UTIs
but two cases of nausea, vomiting and pain post-injection. Study 2
reported 8 UTIs but no adverse events.

Dr. Herrera concluded that Deflux appeared to offer clinically
significant improvement, but that the impact of a non-blinded evaluator
and a single site study should be assessed. He thought that the safety
profile was good, but several statistical issues should be addressed, as
would be noted in the statistical review. Dr. Herrera noted that
long-term safety of more than two years was unknown but was not, in his
opinion, as critical in this entity as in others.

**Judy Chen, statistician,** gave the statistical review. Her primary
concern with the Deflux 1 and 2 studies was whether the observed
improvement was due to the device, spontaneous improvement over time,
regression to the mean, or all of the above. She also noted the
statistical concern that ureter-based success rates would have a larger
variance because outcomes of within-patient ureters are likely to be
correlated. In the randomized control study, protocol deviations
included the fact that two centers were specified but only one entered
patients, endpoint evaluation was not masked in the study, and control
antibiotic treatment compliance was poor. She also commented that since
ureters in the same patient are likely to be correlated, the
statistically highly significant treatment difference is not reliable.
No covariable adjustment was done in the sponsor's per-ureter analysis
or per-patient analysis. Ms. Chen concluded that given these
deficiencies, the data should be reanalyzed by the sponsor and the FDA
to validate the sponsor's statistical conclusion, and that the results
should be interpreted with the other deficiencies in mind.

**Dr. Daniel Schultz, acting director of the Division of Reproductive,
Abdominal, and Radiological Devices,** joined the session at this point
and presented plaques of appreciation to outgoing panel member Craig
Donatucci, M.D., and former panel executive secretary Mary Jo Cornelius.

# Primary Panel Review

**Dr. Naida Kalloo, reviewer for the panel,** stressed that it is
infection, not reflux, that causes damage, and that the sponsors had
demonstrated a success rate for preventing reflux but not infection. She
suggested that the panel discuss the role of antibiotics with and
without the procedure, saying that stopping antibiotics post-treatment
does not necessarily achieve the goal of preventing infection. Dr.
Kalloo urged that patients must have antibiotic coverage throughout the
12-month post-treatment period and until the physician can prove that
reflux is gone. She speculated about long-term patient management, given
the lack of long-term data on success and failure rates, and noted that
the long-term effects on the body are unknown. Dr. Kalloo also saw a
problem in basing approval for the device on a study of 61 patients and
had issues with data collection and insufficient follow-up, which
prompted her to ask whether there was enough information to be
reanalyzed.

**Ms. Chen of the FDA** replied that statistical reanalysis could be
done on the effect of covariables such as age and disease grade on per
patient success in Study 3. Gender, race, and the effect of retreatment
should also be analyzed.

# Panel Discussion of FDA Questions

1\) Should the intended use statement specifically limit the use of
Deflux Injectable Gel to patients with particular grades of VUR?

The majority of the panel agreed that Deflux was a viable treatment
option, based on its demonstrated success rate, for those not wanting
antibiotic treatment for a long period and for those wishing to avoid
major surgery. Treatment of grade IV VUR should not be excluded in the
labeling indications, but parents should be informed that the success
rate for this grade is less than 50% and informed consent should be
mandatory. Physicians should also ensure that this treatment is not used
alone but that antibiotic coverage and/or other means are used to
monitor and treat urinary infection and prevent renal damage. Certain
limitations such as not using the procedure with patients with a
dysfunctional kidney or with patients with inappropriate voiding
problems should also be noted.

*2) Are the results from Study 3 sufficient to assess device safety and
effectiveness, given possible differences between the demographics and
baseline characteristics of the study and the intended U.S. patient
population and the possible differences in device use across
physicians?*

The panel agreed that the study demographics were adequate although
narrow and did not pose a major issue, particularly as reflux is more a
problem in the population studied than in the general population. Larger
panel concerns were the single-site nature of the study, the small
number of patients studied, and the unblinded patient evaluation. There
were concerns over patient compliance in the antibiotic control arm and
whether the control data were therefore sufficient. Several members
thought the data insufficient to establish efficacy and underscored the
lack of long-term data. They urged that more information should be
provided and stratified by age, gender, degree of reflux, and results.

The panel thought the differences among physicians on device use
probably did not warrant concern and that the learning curve for the
device would be relatively short, but it was noted that there were not
enough sites or physicians studied to be definitive.

*3) Does the panel believe that the potential for investigator bias
significantly impacts the conclusions of Study 3 regarding
effectiveness?*

The panel thought the potential for bias did not have a major impact on
post-treatment analysis, but were more concerned about pre-treatment
bias. They suggested a review committee for pretreatment assessment of
VUR grade or a pre and post-treatment assessment and stratification of
results done by committee.

*4) Does the panel believe that Deflux has a favorable risk/benefit
ratio?*

The panel agreed that the risk/benefit ratio was favorable overall but
thought that lack of long-term data made evaluation difficult. Long-term
concerns include migration and the slow failure rate.

5\) Is postapproval study/surveillance needed to address any unresolved
safety and effectiveness issues?

After considerable discussion, the panel agreed that if Deflux is
approved, then there should be more premarketing information collected
and analyzed from the patients who were in the study at two years on
long-term side effects and on antibiotic use. Postmarket surveillance
should be conducted to look at already treated patients and collect
follow-up results through VCUGs at three, 12, and 24 months, ultrasound,
and surveillance urinary cultures. A multicenter, multi-investigator
postapproval study would be desirable to obtain more safety data on
issues such as effect of Deflux on nephritis, transplant, and bladder
cancer. If the device is not approved, more information on those in this
study should be included to make it approvable and thought should be
given to designing a U.S. study to address the incidence of UTI,
nephritis, and bladder pathology after Deflux use.

*6) Should physician training be required prior to use of Deflux?*

The panel consensus was that physician training should not be mandatory,
but physicians should be well versed in treatment of reflux, and a
training video as well as hands-on training should be made available to
physicians who desire it.

*7) Are the proposed "Directions for Use" accurate and comprehensive?*

The panel recommended that labeling and handouts be completely revised,
with specific inclusion and exclusion criteria from the study included
in the labeling, such as exclusions or contraindications for patients
with a Hutch diverticulum and dysfunctional voiding or multiple ureters.
The comment about the length of time that biodegradable material will
remain in place should be struck, and the data presented to the panel
should be used for the one-year human follow-up data. Statements such as
the rate of clinical cure should be struck unless they reflect such
data. More information on age groups, sexes, and reflux grades studied
should be included, as should rates of spontaneous remission. Patient
counseling information should be rewritten to include other therapeutic
options.

**OPEN PUBLIC HEARING**

There were no requests to address the panel.

**FDA CLOSING COMMENTS\
**There were no remarks from FDA representatives.

**SPONSOR CLOSING COMMENTS\
**Sponsor representatives clarified procedures in the Swedish study,
including the fact that antibiotic prophylaxis was given until the
reflux was gone and that patients who failed to comply with protocols
regarding diary notes on antibiotic use in the other studies may still
have complied with the protocol. Sponsors thought that it would be
possible to get follow-up data on Study 3 and probably on Study 2.

**PANEL VOTE**

**Dr. Cooper** read the panel voting instructions and options and
thanked Dr. Naida Kalloo for her review.

A motion was made and seconded to recommend the PMA as approvable with
the following general conditions:

1)  revised labeling

2)  a mandatory post-market study

3)  collection of additional long-term data from existing studies

Vote on the motion initially resulted in a tie, until the Panel Chair
voted in favor of the motion. The conditions were then elaborated as
follows:

1)  The labeling should reflect specific contraindications and inclusion
    and exclusion criteria such as restrictions on patients with a Hutch
    diverticulum, dysfunctional voiding, neurologically impaired
    bladders, and nonfunctioning kidneys, and other changes as reflected
    in the discussions. Informed consent on Grade IV should be required,
    and information on alternative treatment options should be included.
    The need for antibiotic use until reflux is gone should be noted,
    and statistics with respect to age, gender, and degree of reflux
    treated should be included, as should comparison with spontaneous
    remission rates. The risk of UTI should be discussed. This condition
    passed.

2)  A prospective postmarketing study should be conducted at several
    sites in the United States with multiple physicians and sufficient
    number of patients to show efficacy in age and gender subsets.
    Efficacy should be addressed and stratified by age, gender, grade of
    reflux, race, number of treatments, and other specifics to be
    determined by the FDA. Effectiveness should be defined as zero
    reflux. The control could be historical data on the nontreated
    population. This condition passed.

3)  During the premarket period, more long-term data should be collected
    in Studies 1,2, and 3 in terms of efficacy to provide a better
    picture of device performance. Data should be collected on the
    numbers of those reimplanted and those with other surgical
    procedures If these data meet FDA satisfaction, the information can
    be brought to a committee, subcommittee, or panel consultants as
    homework assignments to negotiate labeling. If the European data are
    satisfactory, then an additional postmarket U.S. multicenter study
    can be done, with the U.S. data to be included later in the
    labeling. This condition passed.

The motion to recommend the PMA as approvable subject to the specific
three conditions described above carried by a vote of four to two.

Panel Chair Dr. A. Kalloo thanked the panel, the sponsors, and the FDA
and adjourned the session at 3:30 p.m.

I certify that I attended the Open Session of the Gastroenterology and
Urology Devices Advisory Panel Meeting on October 19, 2000, and that
this summary accurately reflects what transpired.

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

Jeffrey W. Cooper, D.V.M.

Panel Executive Secretary

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

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

Anthony N. Kalloo, M.D.

Panel Chair

Summary minutes prepared by

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

301-587-9722