**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

I. GENERAL INFORMATION

Device Generic Name: Injectable Bulking Agent

Device Trade Name: Deflux^®^ Injectable Gel (referred herein as

"Deflux")

Applicant: Q-Med AB

Seminariegatan 21

SE-752 28 Uppsala

Sweden

Official U.S. Correspondent: Buchanan Ingersoll, P.C.

1776 K Street, N.W., Suite 800

Washington, DC 20006

Premarket Approval (PMA) Number: P000029

Date of Notice of Approval to Applicant: September 24, 2001

II\. INDICATIONS FOR USE

> Deflux is indicated for treatment of children with vesicoureteral
> reflux (VUR) grades II-IV.

III. CONTRAINDICATIONS

> Deflux is contraindicated in patients with any of the following
> conditions:

-   Non-functioning kidney(s)

-   Hutch diverticuli

-   Duplicated ureters

-   Active voiding dysfunction

-   Ongoing urinary tract infection

IV. WARNINGS AND PRECAUTIONS

> [Warning]{.underline}:

-   Do not inject Deflux intravascularly. Injection of Deflux into blood
    vessels may cause vascular occlusion.

> [Precautions]{.underline}:

-   Deflux should only be administered by qualified physicians
    experienced in the use of a cystoscope and trained in subureteral
    injection procedures.

-   The risks of infection and bleeding are associated with the
    cystoscopic procedure used to inject Deflux. The usual precautions
    associated with cystoscopy (e.g., sterile technique, proper
    dilation, etc.) should be followed.

-   The safety and effectiveness of the use of more than 6 ml of Deflux
    (3 ml at each ureteral orifice) at the same treatment session have
    not been established.

-   The safety and effectiveness of Deflux in the treatment of children
    under 1 year of age have not been established.

-   Deflux is supplied prefilled in a 1 ml syringe with a luer lock
    fitting, and is intended for single use only. Carefully examine the
    unit to verify that neither the contents nor the package has been
    damaged in shipment. **DO NOT USE** if damaged. Immediately return
    damaged product to Q-Med AB.

-   Deflux is supplied sterile. Do not re-sterilize, as this may damage
    or alter the product.

-   Deflux is supplied in a syringe ready for use. Never mix Deflux with
    other products.

-   Deflux must be stored at 2C -- 8C, and used prior to the expiration
    date printed on its label. Do not expose Deflux to either sunlight
    or freezing, as this may damage or alter the product. Do not use
    Deflux after its expiration date.

V. DEVICE DESCRIPTION

> Deflux is a sterile, injectable bulking agent composed of microspheres
> of cross-linked dextran ("dextranomer," 50 mg/ml) suspended in a
> carrier gel of non-animal, stabilized hyaluronic acid (17 mg/ml). The
> dextranomer microspheres range in diameter from 80 to 250 microns
> (average diameter approximately 130 microns). Deflux is sold
> pre-filled in a single use, 1 ml syringe. Sterile syringe needles (23
> gauge tip; 35 cm in length) for use during the Deflux injection
> procedure are packaged separately
>
> Deflux is injected submucosally in the urinary bladder in close
> proximity to the ureteral orifice. The injection of Deflux creates
> increased tissue bulk, thereby providing coaptation of the distal
> ureter during filling and contraction of the bladder. The dextranomer
> microspheres are gradually surrounded by body's own connective tissue,
> which provides the final bulking effect.

### VI. ALTERNATIVE PRACTICES AND PROCEDURES

### 

> Vesicoureteral reflux (VUR) is the retrograde flow of urine from the
> bladder into the ureter and kidney. VUR occurs in patients who have an
> anatomical abnormality of the vesicoureteral junction, and is most
> common in children.^1^ If left untreated, the risks of urinary tract
> infection and subsequent pyelonephritis are significantly enhanced,
> which can lead to renal damage and loss of renal function.
>
> Conventional procedures used in the treatment of VUR are:

-   [antibiotic prophylaxis]{.underline} to prevent infection until the
    patient's VUR spontaneously resolves, and

-   [open surgery]{.underline} to reimplant the refluxing ureter(s) into
    the urinary bladder.

### VII. MARKETING HISTORY

> Deflux has been marketed for the treatment of VUR since December 1998
> in the following countries: Australia, Austria, Belgium, Finland,
> France, Germany, Great Britain, Iceland, Italy, The Netherlands,
> Spain, Sweden, and Switzerland. Approximately 1000 patients have been
> treated with Deflux for VUR. Deflux has not been withdrawn from
> marketing for any reason relating to the safety and effectiveness of
> the device.

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VIII\. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

### 

###  

### The safety of Deflux in the treatment of VUR is based on a randomized study in which 39 subjects were treated with Deflux and 21 subjects were treated with antibiotic prophylaxis, and two nonrandomized studies in which a total of 170 subjects were treated with Deflux. The follow-up duration for all three studies was 12 months. See Table 7 for a complete listing of the adverse events observed in this study.

> The following potential risks of subureteral injection procedures were
> not reported in any of the studies: vascular occlusion, urinary
> retention, dysuria, bleeding/hematuria, urgency, and urinary
> frequency.

IX . SUMMARY OF PRECLINICAL STUDIES

[Bench Performance Testing]{.underline}:

> The following bench performance tests were conducted on final,
> sterilized samples of Deflux-filled syringes to evaluate the
> performance characteristics of the device:

-   [Injection time/force testing]{.underline}: Using a syringe plunger
    rod equipped with a finger grip, the Deflux-filled syringe could be
    emptied in 2 minutes with a force of 37 to 38 N. These results
    verified compliance with the injection force specifications.

-   [Syringe leak testing]{.underline}: Syringe leak testing was
    performed to measure the maximum injection force that can be applied
    to Deflux-filled syringes without leaking. The results of this test
    demonstrated leakage at the luer lock fitting at a mean injection
    force of 85 N was applied, confirming that the syringe will not leak
    under normal use conditions.

-   [Drying resistance testing]{.underline}: This testing was performed
    to assess the tendency of the syringe contents to begin drying out
    when prepared for use and left to stand at room temperature for 15
    minutes (to simulate the anticipated conditions of use immediately
    prior to injection). No increases in injection time or force were
    observed, indicating that Deflux is sufficiently resistant to
    drying.

-   [Environmental/transportation testing]{.underline}: Environmental
    and transportation testing (according to ASTM 4169) verified that
    the packaged product can withstand the expected conditions of
    shipping.

[Sterilization, Endotoxin, and Shelf Life Testing]{.underline}:

> Steam sterilization of Deflux-filled syringes was validated to provide
> a sterility assurance level (SAL) of 10^-6^. Testing performed on
> finished product verified that Deflux has endotoxin levels 0.1 EU/ml.
> Accelerated aging testing on sterilized, Deflux-filled syringes
> supports a shelf life claim of 12 months.

[Biocompatibility]{.underline} [Testing]{.underline}:

> Deflux and its component materials were evaluated for biocompatibility
> in accordance with the provisions of the Good Laboratory Practice
> (GLP) regulations, and FDA Blue Book Memorandum #G95-1. Testing
> performed on the final formulation of Deflux included cytotoxicity,
> sensitization, hemolysis, intracutaneous toxicity, muscle implantation
> (90 days), and mutagenicity testing. The results of these tests
> demonstrate that Deflux is non-toxic, non-hemolytic, and
> biocompatible.
>
> Additional testing was conducted in rabbits to evaluate the potential
> for distant migration of the dextranomer microspheres. In this test,
> ^125^Iodine-labeled dextranomer microspheres were submucosally
> injected into the bladders of six rabbits. Samples of blood and
> various tissues were examined for radioactivity at 1 day, 1 week, and
> 4 weeks post-injection. Whole body radiographic scans were also
> performed at these intervals. No distant migration of dextranomer
> microspheres was detected after submucosal injection of Deflux in the
> rabbit bladder wall.

######  [Bladder Submucosa Implantation Testing in Rabbits]{.underline}: {#bladder-submucosa-implantation-testing-in-rabbits .unnumbered}

> A 2-year implant study of Deflux was conducted using 22 rabbits. In
> each rabbit, 1 gram of test article was injected submucosally into
> each of the following bladder sites: right and left bladder neck, and
> right and left bladder wall. The objectives of this study were to
> determine the biocompatibility and migration potential of Deflux when
> implanted into the rabbit bladder submucosa. Follow-up evaluations
> were conducted at 1 week, and 1, 3, 6, 12, and 24 months. In each
> animal, the bladder, pancreas, kidney, liver, lung, draining lymph
> nodes, and brain were removed and examined histologically for
> inflammation, infection, irritation, foreign body responses, tissue
> necrosis, and scarring. Additionally, other organs were examined for
> gross abnormalities.
>
> A total of five rabbits died or were euthanized for reasons unrelated
> to Deflux implantation. This study reported the following significant
> findings:

-   The dextranomer microspheres contained within Deflux remained in the
    tissue in all injection sites for at least 2 years without causing
    any adverse foreign body reaction.

-   The dextranomer microspheres induced a fibrous tissue reaction
    around each microsphere without any adverse inflammatory reaction.

-   The dextranomer microspheres do not appear to migrate to other
    tissues during the 2-year post-implantation period.

-   Deflux appears to be safe when injected into the bladder submucosa
    of rabbits.

######  [Bladder Submucosa Implantation Testing in Dogs]{.underline}: {#bladder-submucosa-implantation-testing-in-dogs .unnumbered}

> A 2-year implant study of Deflux was conducted using 12 dogs. In each
> dog, 2.5 grams of test article was injected submucosally into each of
> the following bladder sites: right and left bladder neck, and right
> and left bladder wall. The objectives of this study were to determine
> the biocompatibility and migration potential of Deflux when implanted
> into the canine bladder submucosa. Follow-up evaluations were
> conducted at 2 weeks, and 3, 6, 12, and 24 months. In each animal, the
> bladder, pancreas, kidney, liver, lung, draining lymph nodes, and
> brain were removed and examined histologically for inflammation,
> infection, irritation, foreign body responses, tissue necrosis, and
> scarring. Additionally, other organs were examined for gross
> abnormalities.
>
> This study reported the following significant findings:

-   The dextranomer microspheres contained within Deflux remained in the
    tissue in all injection sites for at least 2 years without causing
    any adverse foreign body reaction.

-   The dextranomer microspheres induced a fibrous tissue reaction
    around each microsphere without any adverse inflammatory reaction.

-   The dextranomer microspheres do not appear to migrate to other
    tissues during the 2-year post-implantation period.

-   Deflux appears to be safe when injected into the bladder submucosa
    of dogs.

## X. SUMMARY OF CLINICAL STUDIES

[Objectives]{.underline}

> Three single-center, European clinical studies were performed to
> assess the safety and effectiveness of Deflux in the treatment of VUR
> in children. The objectives of these studies were as follows:

-   A randomized study was performed to compare the safety and
    effectiveness of Deflux to antibiotic prophylaxis at 12 months. This
    study was performed at the Ospedale Bambino Gesú (Rome, Italy).

-   A non-randomized study ("Study 1") was performed to investigate the
    safety and effectiveness of Deflux at 12 months. This study was
    performed at the University Children's Hospital (Uppsala, Sweden).

-   An non-randomized study ("Study 2") was performed to investigate the
    safety and effectiveness of Deflux at 12 months. This study was
    performed at the Ospedale Bambino Gesú (Rome, Italy).

[Study Designs]{.underline}

> *Randomized Study*
>
> A prospective, single-center, randomized controlled clinical trial was
> performed to compare the safety and effectiveness of Deflux to
> standard treatment (i.e., antibiotic prophylaxis). Patients were
> randomized (2:1) to either Deflux or standard, long-term, antibiotic
> prophylaxis. Although blinding of the patients and treating physicians
> was not possible in this study, the evaluation of the primary
> effectiveness endpoint (i.e., reflux grade, observed on voiding
> cystourethrogram, "VCUG") was performed by independent radiologists
> who did not know the treatment received by any individual patient.
>
> Effectiveness (i.e., reflux grade on VCUG) was evaluated prior to
> treatment and at 12 months following initial treatment. Additionally,
> reflux grade beyond 12 months was reported for Deflux-treated
> patients.
>
> *Non-Randomized Studies*
>
> The two non-randomized studies were prospective, single-center
> clinical studies, in which all patients received Deflux treatment. For
> these studies, the baseline status of patients served as the
> comparison for the assessment of device outcome.
>
> Effectiveness (i.e., reflux grade on VCUG) was evaluated prior to
> treatment and at 12 months following last treatment. Additionally,
> reflux grade beyond 12 months was reported for Study 1 patients.
>
> *Effectiveness Endpoints*
>
> The primary effectiveness endpoint for each study was change in the
> severity of VUR at 12 months, as observed on VCUG. As indicated below
> in Table 1, VUR severity is classified separately for each ureter into
> one of six reflux grades (Grades 0 -- V) according to the
> International Classification System^1^. Treatment success was defined
> as improvement to reflux grade 0.
>
> Table 1: International Classification System for VUR

  ---------- ------------------------------------------------------------
  **Grade    No reflux.
  0**        

  **Grade    Reflux into the nondilated ureter.
  I**        

  **Grade    Reflux into the pelvis and calyces without dilation.
  II**       

  **Grade    Mild to moderate dilation of the ureter, renal pelvis, and
  III**      calyces with minimal blunting of the fornices.

  **Grade    Moderate ureteral tortuosity and dilation of the pelvis and
  IV**       calyces.

  **Grade    Gross dilation of the ureter, pelvis, and calyces, loss of
  V**        papillary impressions, and ureteral tortuosity.
  ---------- ------------------------------------------------------------

> The secondary effectiveness endpoint was reflux grade beyond 12
> months, which was assessed to evaluate the durability of Deflux
> treatment.
>
> *Safety Endpoints*
>
> The safety endpoints for these three studies were: assessment of the
> severity and frequency of adverse events, urinalysis, serum blood
> chemistry measurements, renal ultrasound examination, intravenous
> pyelogram (IVP), and scintigraphy.
>
> *Patient Selection*
>
> The patient population in the clinical studies consisted of children
> (both boys and girls) who were diagnosed with VUR. The inclusion
> criteria were: patients with grade II-IV reflux in at least one ureter
> (further restricted to grade III-IV reflux in Study 1); duration of
> VUR  6 months; age 1 year; normal serum creatinine levels; and
> patients/parents sign the informed consent form. Exclusion criteria
> for the studies were: serious concomitant illness; prior endoscopic
> treatment of VUR; active UTI; Hutch diverticulum; duplicated ureters;
> and neurogenic bladder.
>
> [Patient Assessments]{.underline}
>
> Prior to enrollment, patients underwent the following screening tests:
> clinical exam/history, VCUG, renal ultrasound examination, IVP
> (*randomized study only*), scintigraphy, serum blood chemistry
> measurements, and urinalysis. Immediately prior to treatment, all
> patients underwent cystoscopy to rule out Hutch diverticuli and
> duplicated ureters. Only those children satisfying the inclusion and
> exclusion criteria were enrolled.
>
> Follow-up for Deflux-treated patients was scheduled for 1 day, 1 week,
> 3 months, and 12 months post-treatment. Three months following the
> initial treatment, patients with persistent reflux were eligible for a
> second Deflux treatment, after which the 1-day, 1-week, and 3-month
> exams were repeated. The 12-month exam was scheduled from the time of
> the initial Deflux treatment in the randomized study, while in Studies
> 1 and 2 it was scheduled from the time of the last Deflux treatment.
> Patients treated with antibiotic prophylaxis in the randomized study
> were only followed at 12 months post-treatment.
>
> The following data were collected post-treatment: clinical examination
> (all time points), assessment of adverse events (all time points);
> VCUG (3 and 12 months), renal ultrasound examination (1 and 12
> months), IVP (12 months, *randomized study only*), scintigraphy
> (12 months, *randomized study only*), serum blood chemistry
> measurements (12 months, *randomized study only*), and urinalysis (3
> and 12 months).
>
> [Demographic Data/Baseline Characteristics]{.underline}
>
> A total of 231 patients were screened and enrolled into the three
> studies. Of these 231 patients, 209 were treated with Deflux
> (randomized study = 39, Study 1 = 50, and Study 2 = 120), 21 were
> treated with antibiotic prophylaxis, and 1 patient assigned to Deflux
> treatment in the randomized study withdrew from the study for personal
> reasons prior to receiving treatment. Of the 230 patients treated with
> either Deflux of antibiotic prophylaxis in these studies, 210 are
> available for analysis at 12 months: 189 Deflux-treated patients
> (randomized study = 39, Study 1 = 43, and Study 2 = 107) and
> 21 antibiotic prophylaxis patients.
>
> Table 2 summarizes the number of patients enrolled, treated, and
> included in the statistical analyses for each study. This table also
> summarizes the reasons for missing data.
>
> Table 2: Study Participants

+----------------+-----------+-----------+--------------+------------+
|                | *         | *         | **Patients   | **         |
|                | *Patients | *Patients | available    | Enrollment |
|                | e         | treated** | for analysis | period**   |
|                | nrolled** |           | @            |            |
|                |           |           | 12           |            |
|                |           |           |  months**^1^ |            |
+----------------+-----------+-----------+--------------+------------+
| **Randomized   | Deflux:   | Deflux:   | Deflux: 39   | Oct. 1997  |
| Study**        | 40        | 39^3^     |              | -- Sept.   |
|                |           |           | AP: 21       | 1998       |
| (Rome, Italy)  | AP^2^: 21 | AP: 21    |              |            |
+----------------+-----------+-----------+--------------+------------+
| **Study 1**    | 50        | 50        | 43^4^        | May 1993   |
|                |           |           |              | -- Aug.    |
| (Uppsala,      |           |           |              | 1994       |
| Sweden)        |           |           |              |            |
+----------------+-----------+-----------+--------------+------------+
| **Study 2**    | 120       | 120       | 107^5^       | Jan. 1995  |
|                |           |           |              | --         |
| (Rome, Italy)  |           |           |              |            |
|                |           |           |              | June 1996  |
+----------------+-----------+-----------+--------------+------------+

> ^1^ This includes patients who attended the 12-month exam and those
> who dropped out of the study at an earlier time due to persistent
> reflux (i.e., failures).
>
> ^2^ AP = Antibiotic Prophylaxis
>
> ^3^ 1 patient randomized to Deflux withdrew prior to treatment.
>
> ^4^ 6 patients who were successfully treated at early follow-up missed
> their 12-month exams, and 1 patient was not evaluated due to protocol
> deviations.
>
> ^5^ 12 patients who were successfully treated at early follow-up
> missed their 12-month exams, and 1 patient was not evaluated due to
> missing baseline reflux grade.
>
> Although the majority of treated patients are included in the 12-month
> effectiveness analysis, there are additional missing data for various
> parameters (e.g., renal ultrasound exam, scintigraphy, etc.) at all
> follow-up visits.
>
> Table 3 summarizes the relevant demographic and baseline
> characteristics of study patients:
>
> Table 3: Demographic and Baseline Characteristics

+----------------+----------+---------+------------+-------+--------+
|                | **Gender | **Mean  | **Racial   | **%   | **Ba   |
|                | distri   | age     | dist       | bila  | seline |
|                | bution** | (range) | ribution** | teral | grad   |
|                |          | in      |            | ref   | e**^1^ |
|                | **(%     | years** | **(%       | lux** |        |
|                | fe       |         | Ca         |       |        |
|                | males)** |         | ucasian)** |       |        |
+----------------+----------+---------+------------+-------+--------+
| **Randomized   | 60.0%    | 4.1     | 100%       | 32.5% | II:    |
| Study**        |          |         |            |       | 37.5%  |
|                | 61.9%    | (1.     | 100%       | 42.9% |        |
| Deflux arm     |          | 0-13.4) |            |       | III:   |
|                |          |         |            |       | 47.5%  |
| (*n=40 pts.*)  |          | 3.9     |            |       |        |
|                |          |         |            |       | IV:    |
| AP arm         |          | (1.     |            |       | 15.0%  |
|                |          | 0-10.0) |            |       |        |
| (*n=21 pts.*)  |          |         |            |       | II:    |
|                |          |         |            |       | 61.9%  |
|                |          |         |            |       |        |
|                |          |         |            |       | III:   |
|                |          |         |            |       | 28.6%  |
|                |          |         |            |       |        |
|                |          |         |            |       | IV:    |
|                |          |         |            |       | 9.5%   |
+----------------+----------+---------+------------+-------+--------+
| ########       | 66.0%    | 4.9     | 100%       | 28.0% | III:   |
|                |          |         |            |       | 70.0%  |
| ##             |          | (1.     |            |       |        |
| ###### Study 1 |          | 0-18.3) |            |       | IV:    |
|                |          |         |            |       | 28.0%  |
| (*n=50 pts.*)  |          |         |            |       |        |
|                |          |         |            |       | V:     |
|                |          |         |            |       | 2      |
|                |          |         |            |       | .0%^2^ |
+----------------+----------+---------+------------+-------+--------+
| **Study 2**    | 74.2%    | 4.4     | 91.8%      | 40.3% | II:    |
|                |          |         |            |       | 30.3%  |
| (*n=119        |          | (0.     |            |       |        |
| pts.*)^3^      |          | 9-15.6) |            |       | III:   |
|                |          |         |            |       | 47.9%  |
|                |          |         |            |       |        |
|                |          |         |            |       | IV:    |
|                |          |         |            |       | 21.8%  |
+----------------+----------+---------+------------+-------+--------+

> ^1^ "Baseline grade" refers to the highest reflux grade of the
> patient's two ureters at enrollment.
>
> ^2^ 1 patient with bilateral grade V reflux was enrolled; this patient
> is a protocol deviation, and is not included in the effectiveness
> analyses.
>
> ^3^ 1 patient enrolled into Study 2 had missing demographic and
> baseline information.
>
> The majority of subjects in each study was female, consistent with
> published reports stating that up to 85% the general VUR population
> occurs in females.^1^ Patients were children, typically between 1 and
> 5 years of age at enrollment. Nearly all study subjects were
> Caucasian. Although these patient populations do not reflect the
> racial diversity of the general U.S. population, the literature
> suggests that VUR is much more prevalent among Caucasian children
> (particularly Caucasian girls).^1^
>
> The study populations are similar with respect to (1) the proportion
> of unilateral versus bilateral reflux and (2) baseline reflux grade,
> with the exception of Study 1 did not enroll any patients with grade
> II reflux (its protocol restricted enrollment to grades III and IV
> reflux). The demographic and baseline characteristics between the
> Deflux and antibiotic prophylaxis arms of the randomized study were
> found to be sufficiently similar to permit statistical comparison of
> these groups.
>
> [Treatment]{.underline}
>
> *Deflux*
>
> In each of the studies, Deflux treatment was performed on an
> outpatient basis. All patients were treated under general anesthesia,
> consistent with other pediatric cystoscopic procedures. The injection
> procedure was performed similarly across the three studies. Using a
> cystoscope, Deflux was injected submucosally into the urinary bladder
> in close proximity to the orifice of each refluxing ureter (at the 6
> o'clock position). Deflux was injected until a prominent bulge
> appeared and the ureteral orifice had assumed a crescent-like shape.
> Each refluxing ureter was injected with a mean volume of 0.8 to 1.1 ml
> per treatment session (range 0.2 to 3.0 ml).
>
> In each study, patients were eligible for a single retreatment if they
> had persistent reflux (i.e., meeting the study inclusion criteria) in
> either ureter on the 3-month VCUG. These patients repeated the same
> 1-day and 1 and 3-month follow-up exams that were required following
> the initial treatment (12-month exams were scheduled from the date of
> initial treatment in the randomized study, and from the date of
> retreatment in Studies 1 and 2). The retreatment rates for the
> randomized study, Study 1, and Study 2 were 28.2%, 20.0%, and 11.8%,
> respectively. Retreatment was performed in an identical fashion as the
> initial treatment. In addition to the single retreatment permitted
> during the 12-month study period, Study 1 patients were allowed to
> receive a third and final injection after the 12-month exam if they
> had persistent reflux (as demonstrated on VCUG).
>
> The only reported problem related to the injection procedure was one
> case of disconnection of the needle from the syringe (reported in the
> randomized study). However, this procedure was successfully completed.
>
> All patients were prescribed prophylactic antibiotics following the
> injection procedure in the event the patient's reflux is not
> immediately corrected. In the randomized study, Deflux patients
> received prophylactic antibiotics until the 1-month exam, after which
> no antibiotics were administered unless a UTI was observed or
> suspected. In Studies 1 and 2, patients received prophylactic
> antibiotics until the 3-month follow-up exam. After that, only those
> Study 1 and 2 patients with persistent reflux received further
> antibiotic prophylaxis.
>
> *Antibiotic Prophylaxis*
>
> In the randomized study, patients randomized to antibiotic prophylaxis
> were prescribed legally marketed antibiotics for the entire 12-month
> follow-up period.
>
> [Data Analysis and Results]{.underline}
>
> *Effectiveness Endpoints*
>
> Due to the design of the randomized study, its results are used for
> the primary assessment of the effectiveness of Deflux treatment. The
> effectiveness results of the two non-randomized studies are reported
> separately as supporting information.
>
> Although each refluxing ureter was separately graded and treated with
> Deflux, the outcomes of ureters within a patient are likely correlated
> (i.e., they are not independent observations). Therefore, all
> statistical analyses of device effectiveness were performed on a
> per-patient basis.
>
> In the randomized study, the evaluation of device effectiveness is
> based on the results of 39 patients who were treated with Deflux and
> 21 patients who underwent antibiotic prophylaxis. The primary study
> endpoint was change in reflux grade from baseline to 12‑months
> post-initial treatment. A patient was classified as a treatment
> success if all refluxing ureters (eligible for treatment under the
> protocol) improved to grade 0. Continued patient follow-up beyond
> 12 months was performed to evaluate the durability of the treatment.
>
> VCUG was obtained at 12 months for 31/39 patients in the Deflux arm
> and 21/21 patients in the antibiotic prophylaxis arm. The remaining
> 8/39 Deflux patients dropped out of the study prior to 12 months due
> to persisting reflux and are categorized as failures. For these Deflux
> and antibiotic prophylaxis cohorts, the percentages of patients
> improved to grade 0 at 12 months are 69.2% (27/39) and 33.3% (7/21),
> respectively. A logistic regression was performed to analyze these
> results, adjusting for the following covariates: baseline grade,
> number of refluxing ureters eligible for treatment, and baseline age.
> This analysis demonstrated that this difference is success rates is
> statistically significant (p=0.0041). Patient gender was initially
> included as an additional covariate in the statistical model. However,
> this variable did not contribute any more information or explanation
> of the variance, and, as a result, was not included in the final
> model. Based on this result, it can be concluded that there was no
> gender effect associated with Deflux treatment.
>
> The 12-month success rates reported in Studies 1 and 2 are similar to
> those reported in the Deflux arm of the randomized study: 23/43
> (53.5%) and 64/107 (59.8%) for Studies 1 and 2, respectively. As with
> the analysis of the randomized study, all Study 1 and 2 patients who
> dropped out prior to the 12-month exam due to persistent reflux are
> categorized as device failures.
>
> Table 4 summarizes the 12-month effectiveness results of each of these
> studies:
>
> Table 4: 12-Month Effectiveness Results

+-----------------+---------------------------+-----------------------+
|                 | **Number (%) Patients     | **Statistical         |
|                 | Improved to Grade 0 @ 12  | significance between  |
|                 | months**                  | groups**              |
+-----------------+---------------------------+-----------------------+
| **Randomized    | 27/39 (69.2%)             | p = 0.0041            |
| Study**         |                           |                       |
|                 | 7/21 (33.3%)              |                       |
| Deflux arm      |                           |                       |
|                 |                           |                       |
| AP arm          |                           |                       |
+-----------------+---------------------------+-----------------------+
| **Study 1**     | 23/43 (53.5%)             | N/A^1^                |
+-----------------+---------------------------+-----------------------+
| **Study 2**     | 64/107 (59.8%)            | N/A                   |
+-----------------+---------------------------+-----------------------+

> ^1^ N/A = Not applicable.
>
> For all three studies, the percentage of patients improved to grade 0
> at 3-month results is similar to the rates reported above for 12
> months.
>
> As indicated by the logistic regression analysis performed on the
> results of the randomized study, the success of Deflux treatment is
> influenced by the following covariates: baseline reflux grade, and
> number of refluxing ureters eligible for treatment. As expected, the
> success rate increases with decreasing baseline grade and for
> unilateral vs. bilateral reflux. For the randomized study, the Deflux
> success rate is higher than the antibiotic prophylaxis rate for each
> of these stratifications. Tables 5 and 6 summarize the effectiveness
> results for each of these stratifications.
>
> Table 5: 12-Month Effectiveness Results vs. Baseline Reflux Grade

+----------------------+---------------------+-----------+------------+
|                      | **% Pts. Improved   |           |            |
|                      | to Grade 0 @ 12     |           |            |
|                      | Months**            |           |            |
+----------------------+---------------------+-----------+------------+
| **Baseline Reflux    | ######              | #######   | ######     |
| Grade**              | ## Randomized Study | # Study 1 | ## Study 2 |
+----------------------+---------------------+-----------+------------+
| Grade II             | Deflux: 93.3% AP:   | N/A       | 73.5%      |
|                      | 46.2%               |           |            |
+----------------------+---------------------+-----------+------------+
| Grade III            | Deflux: 61.1% AP:   | 60.0%     | 58.0%      |
|                      | 16.7%               |           |            |
+----------------------+---------------------+-----------+------------+
| Grade IV             | Deflux: 33.3% AP:   | 38.5%     | 43.5%      |
|                      | 0%                  |           |            |
+----------------------+---------------------+-----------+------------+

> Table 6: 12-Month Effectiveness Results vs. Number of Refluxing
> Ureters

+----------------------+---------------------+-----------+------------+
|                      | **% Pts. Improved   |           |            |
|                      | to Grade 0 @ 12     |           |            |
|                      | Months**            |           |            |
+----------------------+---------------------+-----------+------------+
| **Number of          | ######              | #######   | ######     |
| Refluxing Ureters**  | ## Randomized Study | # Study 1 | ## Study 2 |
+----------------------+---------------------+-----------+------------+
| Unilateral           | Deflux: 76.9% AP:   | 64.5%     | 67.2%      |
|                      | 50.0%               |           |            |
+----------------------+---------------------+-----------+------------+
| Bilateral            | Deflux: 53.8% AP:   | 25.0%     | 48.8%      |
|                      | 11.1%               |           |            |
+----------------------+---------------------+-----------+------------+

> The secondary effectiveness endpoint was change in reflux grade at
> time points greater than 12 months. The objective of this long-term
> assessment was to evaluate the durability of Deflux treatment.
> Although the three clinical studies were not designed to assess the
> safety and effectiveness of Deflux beyond 12 months post-implantation,
> the applicant was able to report the results of additional follow-up
> examinations which were conducted by the investigators of the
> randomized study and Study 1. For the 27 Deflux-treated patients in
> the randomized study who were improved to grade 0 at 12 months, reflux
> grade was assessed via VCUG at a mean follow-up time of 35 months
> post-treatment (range 28 to 39 months). Among this subgroup, all but
> one were still free of reflux. It should be noted that none of these
> patients were retreated following the 12-month exam. Assuming that all
> of the Deflux patients who were study failures at 12 months continue
> to have reflux (worst case scenario), the 35-month success rate is
> 26/39 (66.7%).
>
> Similarly, for the 23 Deflux-treated patients in Study 1 who were
> improved to grade 0 at 12 months, all but one were still free of
> reflux on their most recent VCUG (performed 9 to 67 months
> post-treatment; median = 18 months). Six of these 23 patients received
> a single retreatment following the 12-month exam. Using a
> time-to-event analysis for the entire 50‑patient cohort of Study 1,
> the estimated cure rate at 36 months is 49.4% (standard deviation =
> 10.3%).

Safety Endpoints

> The safety of Deflux was evaluated using the following endpoints:
> assessment of the severity and frequency of adverse events,
> urinalysis, serum blood chemistry measurements, renal ultrasound
> examination, intravenous pyelogram (IVP), and scintigraphy.
>
> A total of 209 Deflux-treated patients were evaluated for adverse
> events in the three clinical studies. Additionally adverse events were
> evaluated in all 21 patients randomized to antibiotic prophylaxis. In
> all, 28 (13.4%) Deflux-treated patients and 1 (4.8%) antibiotic
> prophylaxis patient reported adverse events at some time during the
> 12-month study periods. There were no serious unanticipated adverse
> events or patient deaths reported in any of the studies. Table 7
> provides a description of the observed adverse events.
>
> Table 7: Adverse Events

+----------------+-----------------+-----------------+-----------------+
| **Adverse      | **Randomized    |                 | **Studies 1 &   |
| Event          | Study**         |                 | 2**             |
| Category**     |                 |                 |                 |
|                |                 |                 | **(n=170 pts)** |
+----------------+-----------------+-----------------+-----------------+
|                | **Deflux (n=39  | **AP (n=21      |                 |
|                | pts)**          | pts)**          |                 |
+----------------+-----------------+-----------------+-----------------+
| UTI            | 6 (15.4%)       | 0^1^ (0%)       | 13 (7.6%)       |
+----------------+-----------------+-----------------+-----------------+
| Ureteral       | 1 (2.6%)        | 0^2^ (0%)       | 6 (3.5%)        |
| dilation       |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Na             | 0 (0%)          | 0 (0%)          | 2 (1.2%)        |
| usea/vomiting/ |                 |                 |                 |
|                |                 |                 |                 |
| abdominal pain |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Stomatitis     | 0 (0%)          | 1 (4.8%)        | 0 (0%)          |
+----------------+-----------------+-----------------+-----------------+

> ^1^ Patients randomized to antibiotic prophylaxis were assumed to be
> free of UTI. However, since these patients were not examined as
> frequently as Deflux-treated patients, this value may underestimate
> the true UTI rate.
>
> ^2^ Since patients randomized to antibiotic prophylaxis were not
> examined as frequently as Deflux-treated patients for the occurrence
> of de novo ureteral dilation, this value may underestimate the true
> rate of this complication.
>
> [UTI]{.underline}: Urinalysis was performed at all follow-up
> examinations to assess the frequency of UTI. In the randomized study,
> six Deflux-treated patients reported a total of nine UTIs. These
> nine cases were categorized as asymptomatic bacteriuria (n=4),
> cystitis (n=4), and pyelonephritis (n=1). In Studies 1 and 2, 13
> patients reported a total of 14 UTIs. In all three studies, the UTIs
> typically occurred in patients with persistent reflux, and were
> successfully treated with standard antibiotic therapy. In interpreting
> these results, it is important to note that patients treated with
> Deflux in the randomized study received antibiotic prophylaxis for
> 1‑month following each injection procedure, whereas Study 1 and 2
> patients received antibiotic prophylaxis until the 3-month follow-up
> exam (with additional antibiotic prophylaxis prescribed for those
> patients with persistent reflux).
>
> [Ureteral dilation]{.underline}: Patients were assessed for the
> presence of ureteral dilation pre- and post-treatment by renal
> ultrasound examinations. The overall rate of de novo ureteral dilation
> following Deflux treatment was low. None of the observed cases of de
> novo ureteral dilation required intervention, and most cases resolved
> spontaneously prior to the 12-month exam. It should be noted that, in
> Studies 1 and 2, a total of 18 patients with baseline ureteral
> dilation had no signs of dilation at 12 months.
>
> [Nausea/vomiting/abdominal pain]{.underline}: In Study 1, nausea,
> vomiting, and abdominal pain were reported in two patients immediately
> following the injection procedure. This complication resolved in both
> cases.
>
> [Stomatitis]{.underline}: In the randomized study, one antibiotic
> prophylaxis patient was hospitalized for stomatitis toward the end of
> the 12-month follow-up period. This complication was successfully
> resolved.
>
> The following potential risks of subureteral injection procedures were
> not reported in any of the studies: vascular occlusion, urinary
> retention, dysuria, bleeding/hematuria, urgency, and urinary
> frequency.
>
> IVP, scintigraphy, and serum blood chemistry measurements were
> performed at baseline and 12‑months post-treatment on all patients in
> the randomized study. These studies revealed no clinically significant
> differences between Deflux-treated patients and patients receiving
> antibiotic prophylaxis with regard to the onset of renal scarring,
> parenchymal damage, and changes in kidney size and function.

### 

> [Device Malfunctions/Replacements]{.underline}
>
> No device malfunctions or replacements occurred during the three
> studies.

XI\. CONCLUSIONS DRAWN FROM THE STUDIES

> The bench, animal, and clinical data provide reasonable assurance that
> the benefits of use of Deflux in children with VUR grades II-IV
> outweigh the risk of illness or injury when used as indicated in
> accordance with the directions for use.
>
> The clinical data from patients treated with Deflux demonstrate that
> the treatment cured grade II‑IV reflux in the majority of patients
> with low morbidity. The 12-month effectiveness results for the
> Deflux‑treated patients demonstrate that the treatment response is
> superior to that of standard antibiotic prophylaxis treatment. The
> long-term (i.e., \> 12 months) effectiveness results demonstrate that
> the results of Deflux treatment are durable.
>
> Adverse effects were generally transitory and minor, and consisted
> mainly of UTI and mild ureteral dilation. There were no reports of
> unanticipated adverse events, severe reactions to either the Deflux
> material or the injection procedure, or patient deaths. There was no
> urinary retention or significant decrease in kidney function reported
> among study subjects.

XII\. PANEL RECOMMENDATIONS

> At an advisory meeting held on October 19, 2000, the Gastroenterology
> and Urology Devices Panel recommended that Q-Med's PMA for Deflux be
> approved subject to, and approval by the Center for Devices and
> Radiological Health (CDRH) of, the following conditions:

1.  revised physician labeling (a) indicating the device for use in
    children with grades II-IV reflux, (b) contraindicating patients
    with nonfunctioning kidneys, active voiding dysfunction, duplicated
    ureters, and Hutch diverticuli, (c) summarizing the adverse events
    and other clinical study results, and (d) including sufficient
    patient counseling information on the risks, benefits, and
    limitations of Deflux treatment and alternate therapies for VUR;

2.  collection and analysis of the available, long-term (i.e., \> 12
    months) safety and effectiveness data from existing study subjects;
    and

3.  a postapproval study designed to collect long-term (i.e., 5-year)
    data on the safety and effectiveness of Deflux at multiple U.S.
    sites.

XIII\. CDRH DECISION

> CDRH concurred with the Panel's October 19, 2000, recommendation, and
> issued a letter to Q‑Med, on November 20, 2000, advising the applicant
> that review of its PMA could not be completed until the following
> major deficiencies were adequately addressed: (1) collection and
> analysis of the available, long-term (i.e., \> 12 months) safety and
> effectiveness data from existing study subjects; (2) statistical
> analysis of device effectiveness by relevant stratifications; and (3)
> submission of a postapproval study protocol proposing a 5-year,
> multi-center, U.S. study to investigate the long-term effects of
> treatment. Additionally, the November 20, 2000, letter requested that
> the applicant address the following minor deficiencies: (1) revision
> of the physician labeling to address the concerns raised by the Panel;
> (2) revision of the proposed promotional brochure to be consistent
> with the revised physician labeling; (3) submission of patient
> labeling; (4) statistical analysis of the 12-month effectiveness
> results between the Deflux and control arms of the randomized study
> using logistic regression; (5) clarification of the randomized study's
> patient-level data previously submitted to CDRH in electronic format;
> (6) additional chemistry information regarding the particle size and
> degree of crosslinking of the dextranomer microspheres, the viscosity
> of the carrier gel, and the accuracy of the hyaluronic acid content in
> Deflux; (7) clarification of the stability/shelf life testing,
> including information on the number of samples tested, description of
> how the product will be shipped, and request to limit the labeled
> shelf-life to 12 months; and (8) clarification of the order of the
> packaging and sterilization processes to confirm that the device is
> terminally sterilized.
>
> In amendments received by FDA on May 1 and 15, August 21, and
> September 12 and 18, 2001, Q-Med submitted the required information.
> Specifically, these amendments demonstrate the following: (1) the
> effect of Deflux treatment continues out to at least 2-4 years
> post-treatment, with no serious long-term adverse events; (2) the
> effectiveness of Deflux is superior to that of antibiotic prophylaxis
> for all relevant stratifications; (3) Q-Med will perform the requested
> 5-year post-approval study in the U.S. to assess the long-term safety
> and effectiveness of Deflux; (4) the physician and patient labeling
> have been revised as requested by FDA; (5) the overall effectiveness
> of Deflux is superior (p=0.0041) to that of antibiotic prophylaxis
> when adjusting for all relevant covariates; (6) the electronic files
> for the randomized study have been sufficiently described; (7) the
> chemistry of Deflux and its components have been sufficiently
> described; (8) the stability testing has been sufficiently described
> to justify a 12-month shelf-life; and (9) the sterilization process
> has been changed to permit terminal sterilization of the product.
>
> Q-Med's PMA for Deflux was granted expedited review status on August
> 22, 2000 because FDA believes that an injectable bulking agent for the
> treatment of VUR is a breakthrough technology since it may present a
> clear, clinically meaningful advantage of existing technology (i.e.,
> safer than open surgery and more effective than observation with
> antibiotic prophylaxis).
>
> Inspection of the applicant's manufacturing facility was completed on
> June 14, 2001, and was found to be in compliance with the device
> Quality Systems regulations.
>
> FDA issued an approval order on September 24, 2001.

XIV. APPROVAL SPECIFICATIONS

> [Directions for Use]{.underline}: See the labeling.
>
> [Hazards to Health from Use of the Device]{.underline}: See
> Indications, Contraindications, Warnings, Precautions, and Adverse
> Events in the labeling.
>
> [Postapproval Requirements and Restrictions]{.underline}: See approval
> order.

XV. REFERENCES

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1.  Walsh, P. C., A. B. Retik, E. D. Vaughan, and A. J. Wein, eds.
    [Campbell's Urology]{.underline} (7^th^ Ed.), Vol. 2, pp. 1859-1916,
    W.B. Saunders Co., Philadelphia, 1998.