**MEMORANDUM** DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

**DATE:** May 30, 2003

**FROM:** Brian Strongin, R.Ph., M.B.A., Project Manager, *for*

> Robert L. Justice, M.D., M.S., Director
>
> Division of Gastrointestinal and Coagulation Drug Products,
>
> HFD-180

**SUBJECT:** Briefing Document for the June 26, 2003 Meeting of the

Gastrointestinal Drugs Advisory Committee on Photofrin® (porfimer
sodium) for ablation of high-grade dysplasia in Barrett's Esophagus with
Photodynamic Therapy

**MEETING TIME:** 8:30AM -- 5:00PM

**MEETING LOCATION:** Marriott Washingtonian Center, The Ballrooms,

> 9751 Washingtonian Blvd., Gaithersburg, MD

**Please find enclosed the following items:**

**Attachment One: Medical Officer's Summary**

**Attachment Two: Medical Device Reviewer's Summary**

Thank you for your willingness to participate in the June 26, 2003
Gastrointestinal Drugs Advisory Committee meeting regarding Photofrin
\[porfimer sodium for injection\] for the "ablation of high-grade
dysplasia in Barrett's esophagus among patients who are not considered
candidates for esophagectomy".

You have been provided the draft reviews of the NDA from the Food and
Drug Administration (FDA) medical and device reviewers. The FDA
background package often includes initial reviews and/or preliminary
conclusions and recommendations written by individual FDA reviewers.
These conclusions and recommendations do not necessarily represent the
final position of the individual reviewer, nor do they necessarily
represent the final position of the FDA. The FDA will not take a final
action on the application until input from the advisory committee
process has been considered and all reviews have been finalized.

In order to aid your review of the documents provided by the FDA as well
as Axcan Scandipharm Inc., we would like you to focus on the following
topics:

-   The exclusion of approximately 50% of the patients who were
    determined not to have a diagnosis of high-grade dysplasia by the
    central histopathology laboratory and its relationship to the target
    population;

-   The number of patients who later went on to esophagectomy;

-   The adequacy of a 2-year follow up period for the claim of cancer
    risk reduction in high-grade dysplasia patients;

-   The safety of Photofrin® and photodynamic therapy in this
    population.

-   The contribution of proton pump inhibitors.

The final Advisory Committee questions will be given to you prior to the
actual meeting.

We look forward to your participation and seeing you on June 26, 2003.

**ATTACHMENT ONE**

**MEDICAL OFFICER'S SUMMARY**

DIVISION OF GASTROINTESTINAL AND COAGULATION DRUG PRODUCTS

# [Briefing Document for Gastrointestinal Drug Advisory Committee]{.underline}

NDA: 21-525, N-000

Related NDAs/INDs/PMAs: NDA 20-451; IND 61,011; IND 42,313; IND 25,064;
PMA P990021; PMA P940010.

Sponsor: Axcan Scandifarm Inc.

Drug name: Photofrin® (porfimer sodium)

Pharmacological category: Photosensitizing agent, polyporphyrin oligomer

Proposed indication: Ablation of high-grade dysplasia in Barrett's

###  Esophagus with Photodynamic Therapy

Route of administration: Intravenous injection

Dates submitted: May 31, 2002; September 30, 2002; October 28, 2002;
February 3, 2003.

Action date: August 1, 2003

Medical Reviewer: Edvardas Kaminskas, M.D.

Statistical Reviewer: Milton Fan, Ph.D.

## Executive Summary

1.  Brief Overview of Clinical Program

Patients with Barrett's Esophagus and high-grade dysplasia have a high
risk of developing adenocarcinoma of the esophagus. Three approaches to
management of high-grade dysplasia have been described: esophagectomy,
aggressive surveillance, and mucosal ablation therapy. There have not
been any prospective randomized trials comparing these approaches, and
currently there is no agreement as to which is the best approach.

The Sponsor has submitted the results of three clinical trials in which
photodynamic therapy with Photofrin® was used for mucosal ablation of
high-grade dysplasia. Photofrin® is an approved photosensitizing agent
that is administered intravenously and is innocuous until activated by
light. When target tissues are exposed to laser light at 630 nm, tissue
necrosis occurs by at least two mechanisms, oxygen radical damage and
anoxia due to thrombosis of capillaries. Photodynamic therapy with
Photofrin® is approved for esophageal cancer patients and endobronchial
lung cancer patients.

The principal findings, supporting the indication for photodynamic
therapy with Photofrin® in patients with Barrett's Esophagus and
high-grade dysplasia in patients who refuse esophagectomy and who are in
overall good health, come from a multi-center, randomized, controlled,
partially blinded, 2-arm trial, in which 130 patients were treated with
photodynamic therapy with Photofrin® and 69 patients underwent
aggressive surveillance. Both groups received omeprazole to reduce acid
reflux. Patients in the photodynamic therapy arm underwent up to three
treatment courses, separated by at least 90 days, either because of the
extent of high-grade dysplasia (the longest segment that could be
treated was 7 cm) or lack of response. The dose of Photofrin® was
standard in this trial, as in all other Photofrin® trials. Light
delivery systems consisted of endoscopically placed fiber-optic
filaments tipped with cylindrical diffusers and of centering balloons of
various lengths and types. Patients were followed every 3 months until
four consecutive endoscopic results were negative for high-grade
dysplasia and then semi-annually until the last enrolled patient had
completed at least 24 months of follow-up evaluation after
randomization. The length of follow-up ranged from 2 to 3.6 years.

The two open-label, uncontrolled, single-center studies provided
efficacy results on 86 patients with high-grade dysplasia who had been
followed for a minimum of 12 months after randomization. In addition,
these studies provided safety results on 99 additional patients who did
not have high-grade dysplasia, and who were treated with Photophrin®
photodynamic therapy for low-grade dysplasia, metaplasia, or superficial
adenocarcinoma.

The average age of patients in the three trials was 66 years, 81% were
males, 99% were of the Caucasian race, and 71% were former or current
smokers. These characteristics are typical of patients with Barrett's
Esophagus with high-grade dysplasia and of patients with esophageal
adenocarcinoma.

2.  Efficacy

The primary efficacy endpoint, assessed after a minimum follow-up of 24
months, was the complete ablation of high-grade dysplasia with regrowth
of normal squamous epithelium (Complete Response or CR1), of squamous
epithelium with some areas of metaplasia (CR2), or of squamous
epithelium with some areas of low grade dysplasia, indefinite dysplasia,
or metaplasia (CR3). Photofrin® photodynamic therapy resulted in a
Complete Response in 81.5% of treated patients, while omeprazole alone
resulted in 39.1% Complete Response (difference between groups was
significant, with p\<0.0001).

Secondary efficacy endpoint analyses showed that 1) the most common type
of Complete Response was CR1 in the Photofrin® photodynamic therapy
group and CR3 in the omeprazole only group, 2) the median duration of
Complete Response was 987 days in the Photofrin photodynamic therapy
group and 98 days in omeprazole only group (difference significant, with
p\<0.001), 3) while the median time to progression to cancer could not
be assessed, the percentage of patients who progressed to cancer was
about twice as high in the omeprazole only group compared to Photofrin®
photodynamic therapy group, and 4) a greater percentage of patients had
not progressed to cancer or had another therapeutic intervention in the
Photofrin® photodynamic therapy group than in the omeprazole only group
(only 16% of the omeprazole only group remained in follow-up at the end
of the study compared to 62% of the Photofrin photodynamic therapy
group). Survival time could not be estimated for either group.

Additional analyses showed that patients who failed to achieve a
Complete Response in either group of patients had about a ten-fold
higher risk of progression to cancer than patients who achieved a
Complete Response.

The results of the supporting studies were consistent with the results
of the primary trial.

3.  Safety

The major side-effects of Photofrin photodynamic therapy were acute
effects related to the light treatment (such as chest pain, abdominal
pain, fever, nausea, vomiting, odynophagia and dysphagia), skin
photosensitivity reactions, and treatment-related esophageal strictures
requiring dilations (in about 38% of patients).

None of the deaths were related to treatment and none was due to
adenocarcinoma of the esophagus. Most common serious adverse events were
gastrointestinal disorders and dehydration. There were two patients who
had esophageal perforations, one of whom underwent an emergency
esophagectomy. One patient withdrew from the study because of an anxiety
reaction before photodynamic therapy. Other withdrawals were not related
to high-grade dysplasia or to treatment.

4.  Dosing

The standard dose of Photofrin® was 2 mg/kg, and this dose was
administered to over 95% of patients. The prescribed 630nm laser light
dose was 130 J/cm, and 92% of patients received this dose.

5.  Special Populations

Differences in pharmacology, safety, or effectiveness have not been
found with respect to gender, race (Caucasians vs. Asians), or age. A
waiver for pediatric studies was requested on the basis that Photofrin®
is designated as an Orphan Drug. There are no adequate and
well-controlled studies in pregnant women or nursing mothers.

***[Clinical Review]{.underline}***

1\. Background

1.  High-grade dysplasia (HGD) in Barrett's Esophagus may progress to
    adenocarcinoma of the esophagus, a neoplasm that carries a poor
    prognosis and that has been dramatically increasing in incidence.
    Risk of adenocarcinoma in HGD patients is broadly stated as 25%, but
    different studies have reported development of cancer in 16% to 59%
    of HGD patients who were followed with endoscopic surveillance for 3
    to 7 years. At the present time, there is no consensus on the best
    management of HGD.

-   An esophagectomy is advocated by some, as up to 50% of the resected
    specimens demonstrate previously unrecognized adenocarcinoma.

-   Aggressive surveillance every 3 months, if esophagectomy is not
    performed, is recommended by the American College of
    Gastroenterology. The purpose of surveillance is to detect cancer at
    an early and potentially curable stage. The endpoint of surveillance
    is esophagectomy for cancer. Several retrospective studies clearly
    suggest that Barrett's esophagus patients in whom adenocarcinoma was
    detected in a surveillance program had a dramatically improved
    5-year survival compared to similar patients who did not undergo
    routine endoscopic surveillance. Surveillance consists of
    four-quadrant biopsy specimens at 2-cm intervals along the entire
    length of Barrett's esophagus.

-   A third option is [mucosal ablation]{.underline} therapy by
    photodynamic therapy, thermal therapy or endoscopic mucosal
    resection.

-   There have not been any prospective randomized trials comparing the
    efficacies and the benefit/risk ratios of these approaches.

The Sponsor is seeking the following indication for photodynamic therapy
(PDT) with Photofrin®: ["the ablation of HGD in Barrett's Esophagus
among patients who refuse esophagectomy and who are in overall good
health."]{.underline} In support of this indication the Sponsor has
presented the results of three clinical trials. The principal findings
are from a multi-center, randomized, controlled, 2-arm, partially
blinded study (PHO BAR 01) in which 130 HGD patients in one arm were
treated with PDT using Photofrin® as a photosensitizing agent and an
endoscopically administered laser light as the therapeutic agent causing
the destruction of HGD, while 69 HGD patients in the other arm underwent
a rigorous surveillance program. Patients in both arms were treated with
omeprazole to reduce acid reflux. The two arms will be referred to as
[PHOTOFRIN PDT + OM]{.underline} arm, and [OM Only]{.underline} arm,
respectively.

> The results of the principal study are supported by the results of two
> single-center, partially blinded, uncontrolled studies (TCSC 93-07 and
> TCSC 96-01) in which patients with HGD, as well as patients with
> low-grade dysplasia, localized adenocarcinoma, and BE without
> dysplasia or carcinoma, were treated with PHOTOFRIN PDT and
> omeprazole. In the supporting studies efficacy endpoints were assessed
> in patients with HGD, and safety aspects were assessed in all treated
> patients irrespective of the diagnosis.

2\. Photodynamic therapy: Photofrin® and light delivery systems

Photodynamic therapy (PDT) is based on systemic administration of
photosensitizing agents that are retained with some selectivity in
rapidly proliferating and malignant tissues. When target tissues are
exposed to appropriate wavelength laser light, the resulting tissue
necrosis is thought to occur by two mechanisms, direct cytotoxicity by
oxygen radicals and anoxia resulting from thrombosis of tumor
capillaries.

[Photofrin®:]{.underline} The only approved photosensitizing agent for
PDT is Photofrin® (porfimer sodium) for Injection. Photofrin is a
complex mixture of porphyrin oligomers joined by ether and ester
linkages, primarily dimers and trimers, but including molecular species
as big as octamers. Oligomer aggregation/disaggregation reactions occur
spontaneously in aqueous solution and result in mixtures of oligomers,
all of which are active as photosensitizing agents. Molecular weights of
oligomers in porfimer sodium range from 1178 to 4659 daltons. The
starting material for porfimer sodium is hemin, which is prepared from
porcine hemoglobin solution.

Photofrin® is administered intravenously. It is 90%-bound to serum
proteins, distributed in tissues within 24 hours, and excreted very
slowly, with a first-phase half-life of about 9 days and a second-phase
half-life of about 36 days. Photofrin® monomers are degraded to
bilirubin and excreted into bile. An important aspect of Photofrin®
breakdown is photo-bleaching, which reduces the risks of skin
photosensitivity. Photofrin® is innocuous until activated by light.

[Present indications:]{.underline} Photofrin® PDT is approved for
treatment of patients with completely obstructing esophageal cancer,
patients with obstructing endobronchial non-small lung cancer, and
patients with micro-invasive endobronchial non-small lung cancer. The
standard dose of Photofrin® is 2 mg/kg of body weight.

There appear to be no gender differences, race differences (Photofrin®
has been studied in Caucasian and Japanese patients, but the numbers of
patients were small), or differences between volunteers and patients.
There are no known drug-drug interactions, except with concomitant use
of other photosensitizing agents, or drugs that are excreted in bile.
However, photosensivity due to Photofrin® is so overwhelming that it
dwarfs the effects of any other photosensitizers. There are no known
interactions with omeprazole.

[PDT:]{.underline} In photodynamic therapy, light activation is
performed with red light at 630 nm wavelength 40 to 50 hours after
Photofrin® injection, at which time Photofrin® has largely cleared from
a variety of normal tissues, but has been retained by neoplastic
tissues, skin, and organs of the reticuloendothelial system. Because the
normal esophagus tends to collapse when empty, light delivery systems
have been developed that consist of endoscopically placed fiber-optic
filaments tipped with cylindrical diffusers and of centering balloons of
various lengths and types. Regular light laser sessions were performed
using balloons with window lengths of 3 cm, 5 cm, and 7 cm. HGD areas
longer than 7 cm required additional courses of treatment. The specified
light dose was 130 J/cm. Nodules within HGD were pre-treated with
short-fiber optic diffusers (\<2.5 cm) with a light dose of 50 J/cm.

3.  Study population

> In the pivotal PHO BAR 01 study, a total of 485 patients with HGD were
> screened at 30 centers in the United States, Canada, and Europe. The
> plan was to enroll 200 patients; 208 patients were enrolled. The
> reasons for exclusion are shown in Reviewer's Table 1. It should be
> noted that 237 patients were excluded because the diagnosis of HGD was
> not confirmed by the Central Reference Laboratory. The excluded
> patients had metaplasia, indefinite dysplasia, low-grade dysplasia or
> carcinoma; all had been diagnosed with HGD and referred for Photofrin
> PDT. This is an important finding that raises the possibility that
> patients without HGD may be treated unnecessarily with Photofrin® PDT.
> The methods used in diagnosis of HGD will be described in the next
> section.
>
> **[Reviewer's Table 1. Reasons for Patient Exclusion from
> Enrollment]{.underline}**

+-----------------------------------+-----------------------------------+
| **Total screened**                | **485**                           |
+-----------------------------------+-----------------------------------+
| **Total randomized to treatment** | **208 (42.9%)**                   |
+-----------------------------------+-----------------------------------+
| **Total not randomized**          | **277 (57.1%)**                   |
|                                   |                                   |
| -   **No high-grade dysplasia**   | **237 (85.6% of 277)**            |
|                                   |                                   |
| -   **Other screening criteria    | **13 (4.7% of 277)**              |
|     not met**                     |                                   |
|                                   | **25 (9.0% of 277)**              |
| -   **Declined participation**    |                                   |
|                                   | **2 (0.7% of 277)**               |
| -   **Other**                     |                                   |
+-----------------------------------+-----------------------------------+

> [Inclusion criteria]{.underline} were few: HGD as assessed by the
> central reference laboratory, at least 18 years of age, not pregnant,
> practicing birth control if of childbearing potential, and signed
> informed consent. [Exclusion criteria]{.underline} were more
> extensive: cancer of the esophagus, history of any cancer within 5
> years, prior PDT to esophagus, esophageal strictures unresponsive to
> dilation, acute or severe chronic illness, contraindications to
> analgesia, esophagoscopy or omeprazole, porphyria, esophageal ulcers
> or varices, and abnormal renal, hepatic or hematologic laboratory
> values.
>
> The average age of patients was 66 years (range, 36 to 88 years), 85%
> were males, 99% were Caucasians, and 71% were former or current
> smokers. The composition of study patient population was similar to
> that of patients with Barrett's Esophagus with HGD, and of patients
> with adenocarcinoma of the esophagus. Mean duration of BE was about 3
> years and mean duration of HGD was 6 months. Most patients had hiatal
> hernias, about 30% had nodules, about 5% had strictures, and about 5%
> had ulcers. Almost all patients had previous medical therapy; a few
> patients had prior surgery.

4.  Diagnosis of HGD

> Since the primary efficacy endpoint of the study depended on
> histological diagnoses, all biopsy slides were read by three
> pathologists at the Central Reference Laboratory, which was the GI
> Biopsy Laboratory at the University of Washington Medical Center. As
> part of the PHO BAR 01 study, a sub-study was carried out to assess
> the intra-rater and inter-rater percent agreement on histologic
> diagnoses. The intra-rater agreement was very high (average 96%;
> range, 92% to 99%). The inter-rater agreement was generally high: 88%
> for high-grade dysplasia, 96% for cancer, 92% for high-grade dysplasia
> or cancer, 85% for dysplasia (low-grade or high-grade), and 99% for
> Barrett's esophagus (metaplasia). Obscuring inflammation due to acid
> reflux had the greatest impact on inter-rater agreement of HGD.

5.  Treatment assignment and disposition

> Of the 208 patients enrolled in the PHO BAR 01 study (ITT population),
> 138 were randomized to the PHOTOFRIN + OM group and 70 to the OM Only
> group. The Evaluable population consisted of 130 patients in the
> PHOTOFRIN + OM group and of 69 patients in the OM Only group. The
> reasons for exclusion of eight patients from the ITT PHOTOFRIN + OM
> group were: 1) one patient had low grade dysplasia at baseline and was
> randomized by error, 2) one patient had was found to have an
> adenocarcinoma at baseline and was randomized by error, 3) three
> patients withdrew consent, 4) one patient received the Photofrin®
> injection but did not undergo PDT because of procedure-related
> anxiety, and 5) two patients received the first course of treatment
> but were discontinued because invasive esophageal cancer could not be
> excluded by esophageal ultrasound. One patient in the ITT OM Only
> group was excluded from the Evaluable population because the patient
> chose to undergo an esophagectomy instead of taking omeprazole.
>
> The efficacy results will be presented for the Evaluable population
> rather than for the ITT population, because the inclusion of untreated
> patients as non-responders in a relatively small population base will
> serve to confuse rather than to clarify the effect of PHOTOFRIN PDT.
> The results, as recalculated for the ITT population, are presented in
> the Appendix. The Safety population consisted of all the ITT patients
> who had at least one Photofrin injection in the PHOTOFRIN + OM group
> and one week of omeprazole treatment in the OM Only group. Treatment
> assignment and patient disposition is shown in Reviewer's Table 2.
>
> **[Reviewer's Table 2. Treatment assignment and disposition of
> patients]{.underline}**

+-----------------------+-----------------------+-----------------------+
| **Patient             | **PHOTOFRIN PDT +     | **OM Only**           |
| population**          | OM**                  |                       |
|                       |                       | **Number of patients  |
|                       | **Number of patients  | (%)**                 |
|                       | (%)**                 |                       |
+-----------------------+-----------------------+-----------------------+
| **Intent-to-treat     | **N = 138 (100%)**    | **N = 70 (100%)**     |
| (number of patients   |                       |                       |
| randomized)**         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Evaluable**         | **N = 130 (94%)**     | **N = 69 (99%)**      |
+-----------------------+-----------------------+-----------------------+
| **Safety**            | **N = 133 (96%)**     | **N = 69 (99%)**      |
+-----------------------+-----------------------+-----------------------+
| **Completed study     | **N = 81 (60.9%)**    | **N = 11 (15.7%)**    |
| (minimum 24 months)** |                       |                       |
+-----------------------+-----------------------+-----------------------+

> The reasons for the low percentages of patients completing the study
> will be described below under efficacy endpoints and outcomes.

6.  PDT Treatment

> Photofrin® was administered I.V. at a dose of 2.0 ± 0.02 mg/kg to over
> 95% of patients. Laser light at 630 nm was administered 40 to 50 hours
> after drug administration. The prescribed dose was 130 J/cm; 92% of
> patients received doses between 130 and 140 J/cm at any one of the
> treatment courses. The remainder received lower or higher doses.
>
> Each course consisted of one or two laser light sessions. The first
> session included a balloon light treatment in all patients and
> pre-treatment of nodules in some patients. A second laser light
> session 2 days later treated skip areas. Patients were permitted to
> receive at most 3 courses of treatment separated by no less than 90
> days. The reasons for additional courses of treatment were the length
> of HGD (a maximum of 7 cm could be treated in one course) and
> unsatisfactory response. Reviewer's Table 3 (below) shows the number
> of courses and the number of sessions administered to the Evaluable
> population.
>
> **[Reviewer's Table 3. Photodynamic Therapy Treatment in Evaluable
> Population in PHO BAR 01 Study]{.underline}**

+------------------------+---------------+-------------+-------------+
| **Laser light          | **Course 1**  | **Course    | **Course    |
| sessions**             |               | 2**         | 3**         |
|                        | **N = 130     |             |             |
| **Number of patients   | (100%)**      | **N = 89    | **N = 42    |
| (%)**                  |               | (100%)**    | (100%)**    |
+------------------------+---------------+-------------+-------------+
| **First laser light    | **35          | **27        | **12        |
| session**              | (26.9%)**     | (30.3%)**   | (28.6%)**   |
|                        |               |             |             |
| -   **Pretreatment of  | **129         | 89.         | 41. **      |
|     nodules**          | (99.2%)\***   |  **(100%)** | (97.6%)\*** |
|                        |               |             |             |
| -   **Balloon light    | **60          | **49        | **21        |
|     treatment**        | (46.2%)**     | (55.1%)**   | (50%)**     |
|                        |               |             |             |
| **Second laser light   |               |             |             |
| session**              |               |             |             |
|                        |               |             |             |
| -   **Treatment of     |               |             |             |
|     skip areas**       |               |             |             |
+------------------------+---------------+-------------+-------------+

> **\*Excludes patients who received PDT without balloon.**
>
> All patients in both arms of the study received omeprazole 20 mg twice
> daily.

7.  Follow-up

> All patients were to be followed every 3 months until 4 consecutive
> quarterly follow-up endoscopic results were negative for HGD, and then
> semi-annually until the last enrolled patient had completed at least
> 24 months of follow-up evaluation after randomization. The length of
> follow-up ranged from 2 to 3.6 years.

8.  Efficacy results

> Efficacy analysis in the PHO BAR 01 study was performed after a
> minimum follow-up of 24 months after the last patient was randomized.

-   The [primary efficacy endpoint]{.underline} was the complete
    ablation of HGD, with re-growth of only normal squamous epithelium
    (complete response 1 or CR1), of squamous epithelium with some areas
    of metaplasia (CR2 response), or of squamous epithelium with some
    areas of low-grade dysplasia, indefinite dysplasia, or metaplasia
    (CR3 response).

-   The primary efficacy analysis was based on the clinical response
    (CR) rate at any one of the evaluations during the 24-month
    follow-up periods. The percentages of responding patients in the two
    treatment arms are shown in Reviewer's Table 4.

**[Reviewer's Table 4. Clinical Response After a Minimum Follow-up of 24
Months]{.underline}**

+-----------------------------+----------------------+-----------------+
| **Response**                | **PHOTOFRIN PDT +    | **OM Only**     |
|                             | OM**                 |                 |
+-----------------------------+----------------------+-----------------+
| **CR1 + CR2 + CR3**         | **106/138            | **27/70         |
|                             | (76.8%)\***          | (38.6%)\***     |
| **Intent-To-Treat           |                      |                 |
| population**                |                      |                 |
+-----------------------------+----------------------+-----------------+
| **CR1 + CR2 + CR3**         | **106/130            | **27/69         |
|                             | (81.5%)\***          | (39.1%)\***     |
| **Evaluable population**    |                      |                 |
+-----------------------------+----------------------+-----------------+

**\*Differences between PHOTOFRIN PDT and OM Only groups are significant
with p\<0.0001.**

-   [Further analysis during the review showed that Complete Response
    was not only an improvement in the anatomy of the esophageal mucosa
    but appeared to correlate with a decreased risk of development of
    carcinoma.]{.underline} Reviewer's Table 5 demonstrates the
    following findings:

1)  Non-responders in both PHOTOFRIN + OM and OM Only groups had a very
    high percentage of patients who progressed to cancer, about 45% to
    50%.

2)  Responders in both groups had a much lower percentage of patients
    who progressed to cancer, about 4% to 6%.

3)  The percentages of patients who progressed to cancer were about
    twice as high in the control group (OM Only) as in the PHOTOFRIN
    PDT + OM group.

**[Reviewer's Table 5. Progression to Cancer Among Responders and
Non-Responders in the Evaluable Populations with a Minimum Follow-up of
24 Months]{.underline}**

+----------------------+-----------------------+-----------------------+
| **Patient group\***  | **Total number of     | **Total number who    |
|                      | patients**            | progressed to         |
|                      |                       | cancer**              |
+----------------------+-----------------------+-----------------------+
| **PHOTOFRIN PDT**    | **130**               | **18 (13.8%)**        |
|                      |                       |                       |
| -   **CR1+CR2+CR3**  | **106**               | **6 (5.7%)**          |
|                      |                       |                       |
| ```{=html}           | **24**                | **12 (50%)**          |
| <!-- -->             |                       |                       |
| ```                  |                       |                       |
| -   **No response**  |                       |                       |
+----------------------+-----------------------+-----------------------+
| **OM Only**          | **69**                | **20 (29.0%)**        |
|                      |                       |                       |
| -   **CR1+CR2+CR3**  | **27**                | **1 (3.7%)**          |
|                      |                       |                       |
| -   **No response**  | **42**                | **19 (45.2%)**        |
+----------------------+-----------------------+-----------------------+

**\*Evaluable populations.**

The above results should be considered as preliminary, since the numbers
of patients are small and the follow-up periods are relatively short.

-   [Secondary efficacy endpoint]{.underline}: The Quality of CR. Most
    of the responders in the PHOTOFRIN PDT + OM group had a CR1
    response, while most of the responders in the OM Only group had a
    CR3 response (as shown in Reviewer's Table 6). Most of the responses
    in both arms were consistent from one evaluation to the next, except
    as response failure occurred. It was not possible to determine
    whether the quality of CR correlated with failure to progress to
    cancer because of the small number of responders who progressed to
    cancer.

**[Reviewer's Table 6. Relative Frequencies of Responses in the
Evaluable Populations]{.underline}**

+-----------------------+-----------------------+-----------------------+
| **Quality of          | **PHOTOFRIN PDT +     | **OM Only**           |
| response**            | OM**                  |                       |
|                       |                       | **N = 69**            |
|                       | **N = 130**           |                       |
+-----------------------+-----------------------+-----------------------+
| **CR1**               | **72 (55.4%)**        | **5 (7.2%)**          |
+-----------------------+-----------------------+-----------------------+
| **CR2**               | **9 (6.9%)**          | **5 (7.2%)**          |
+-----------------------+-----------------------+-----------------------+
| **CR3**               | **25 (19.2%)**        | **17 (24.6%)**        |
+-----------------------+-----------------------+-----------------------+
| **No response**       | **24 (18.5%)**        | **42 (60.9%)**        |
+-----------------------+-----------------------+-----------------------+

-   [Secondary efficacy endpoint:]{.underline} Duration of Response.
    Kaplan-Meier method was used for estimation of duration of response.
    Median durations are shown in Reviewer's Table 7.

**[Reviewer's Table 7. Median Duration months of Response after a
Minimum follow-up of 24 months]{.underline}**

+-----------------+-------------------+-----------------+--------------+
| **Complete      | **PHOTOFRIN PDT + | **OM Only**     | **Log-rank   |
| response**      | OM**              |                 | p-value**    |
|                 |                   | **Median        |              |
|                 | **Median (days)** | (days)**        |              |
+-----------------+-------------------+-----------------+--------------+
| **CR1**         | **316**           | **84**          | **0.1905**   |
+-----------------+-------------------+-----------------+--------------+
| **CR1 + CR2**   | **478**           | **184**         | **0.5182**   |
+-----------------+-------------------+-----------------+--------------+
| **CR1 + CR2 +   | **987**           | **98**          | **\<0.001**  |
| CR3**           |                   |                 |              |
+-----------------+-------------------+-----------------+--------------+

-   [Secondary efficacy endpoint:]{.underline} Time to progression to
    cancer. This endpoint was defined as the day 50% of the patients had
    documented progression to cancer. Since 50% of patients in either
    group had not progressed to cancer, this endpoint could not be
    assessed. About 70% of patients who progressed to cancer in both the
    PHOTOFRIN PDT group and in the OM Only group did so within 12 months
    from the start of treatment. A Kaplan-Meier plot of the time to
    progression to cancer is shown below.

![](media/image1.png){width="5.9in" height="5.14375in"}

-   [Secondary efficacy endpoint]{.underline}: Time to Treatment
    Failure. This endpoint was a composite of 1) progression to cancer,
    and 2) any intervening therapy other than the randomized study
    treatment. A Kaplan-Meier plot of this endpoint is shown below. The
    median Time to Treatment Failure could not be estimated for the
    PHOTOFRIN PDT group, and was 670.0 days for the OM Only group.

![](media/image2.png){width="5.083333333333333in"
height="4.408333333333333in"}

Reviewer's Table 8 shows an accounting of the numbers of patients during
the study that may help understanding the above Kaplan-Meier plot.

**[Reviewer's Table 8. Patient Outcomes in Evaluable
Populations]{.underline}**

  ----------------------- ----------------------- -----------------------
  **Patients**            **PHOTOFRIN PDT + OM**  **OM Only**

  **Evaluable             **130**                 **69**
  population**                                    

  **Progressed to         **18**                  **20**
  cancer**                                        

  **Had another           **18**                  **21**
  therapeutic                                     
  intervention**                                  

  **Deaths, AEs,          **13**                  **17**
  discontinued for                                
  administrative                                  
  reasons**                                       

  **Total discontinued    **49 (37.7%)**          **58 (84.1%)**
  (%)**                                           

  **Total remaining at    **81 (62.3%)**          **11 (15.9%)**
  end of follow-up (%)**                          
  ----------------------- ----------------------- -----------------------

-   In the PHOTOFRIN PDT group, 18 patients had progressed to cancer,
    and another 18 had another therapeutic intervention because of
    persistence or recurrence of HGD. Thus, 36 patients were
    discontinued because they had failed PHOTOFRIN PDT (27.7% of the
    evaluable population).

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-   In the OM Only group, 20 patients had progressed to cancer, and 21
    had a therapeutic intervention for HGD. Since this was the
    surveillance group, the latter patients did not experience treatment
    failure but decided to undergo some form of active treatment.
    Anxiety was stated to be the motivational force in some cases. A
    total of 41 patients were discontinued from the study for these
    reasons (59.4% of the evaluable population).

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-   Administrative discontinuations, deaths, and adverse events
    accounted for discontinuation of additional 13 patients in the
    PHOTOFRIN PDT group and of additional 17 patients in the OM Only
    group.

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```
-   By the end of the follow-up period the two patient populations were
    far more out of balance than the 2:1 ratio at the start of the
    study.

There are several implications of these statistics:

-   At least in this study, it was difficult to maintain patients in a
    control treatment arm, as patients opted for active treatment.

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```
-   Treatment failure due to intervening therapy in the control arm is
    different from that in the PHOTOFRIN PDT arm, because it is not a
    failure of treatment, but the choice to undergo active treatment
    instead of continuing surveillance. By contrast, the intervening
    therapy in the PHOTOFRIN PDT arm was for recurrence of HGD. In the
    PHOTOFRIN PDT group, 9 of the 18 patients had intervening therapy in
    the 12 -- 18 month period after the start of therapy, 3 had in the
    18 -- 24 month period, and the rest between 2 and 3 years after the
    start of therapy. In the OM Only group approximately equal groups of
    patients had intervening therapy in each successive 6-month period.

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```
-   Combining the two types of events into one endpoint of Treatment
    Failure makes the Kaplan-Meier plots of the two patient groups
    difficult to understand.

[Secondary endpoint:]{.underline} Survival Time. This endpoint could not
be estimated. There were only 3 deaths in both treatment groups during
this period, and none of them were due to adenocarcinoma of the
esophagus or to treatment.

9.  Efficacy results in Supporting Studies

Two open-label, uncontrolled, single-center studies provided results on
86 patients with HGD treated with PHOTOFRIN PDT and omeprazole, and
followed for a minimum of 12 months. The results of the supporting
studies were consistent with the results of the principal trial.

-   The overall complete response (CR1 + CR2+ CR3) in the two studies
    was 94.2%.

-   The median duration of complete response was 391 days in one study,
    and could not be estimated in the second one.

-   Progression to cancer occurred in 11 (12.8%) of patients during a
    12-month follow-up.

-   Response failures (includes patients who progressed to cancer and
    patients who had other intervening therapy) occurred in 28/86
    (32.6%) of patients during a minimum follow-up of 12 months.

-   Survival time could not be estimated in either study. Six patients
    died in the two studies. None of the deaths were related to
    adenocarcinoma of the esophagus or to treatment.

10. Other Intervening Therapies (in Treatment Failure patients) in the
    PHO BAR 01 trial were as follows:

-   In PHOTOFRIN PDT group diagnosed with cancer, esophagectomy was the
    most common procedure. Other procedures were PDT bare fiber, EMR
    with or without PDT, and radiation therapy with or without
    chemotherapy.

-   In PHOTOFRIN PDT group with persistent HGD, esophagectomy was the
    most common procedure, followed by contact YAG laser, an additional
    course of PDT, plasma coagulator, Nd:YAG laser, heater probe
    ablation, mucosal resection, argon beam, and electrocautery.

-   In OM Only group diagnosed with cancer, PHOTOFRIN PDT and
    esophagectomy were the most commonly used therapeutic procedures.
    The other therapies were as listed above for the PHOTOFRIN PDT
    group.

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```
-   In OM Only group diagnosed with persistent HGD, PHOTOFRIN PDT was
    used in 75% of patients and esophagectomy in the rest.

11. Safety

The Safety population consisted of 318 patients treated with PHOTOFRIN
PDT from the principal multi-center, controlled study and the two
single-center, uncontrolled studies. The latter studies included 100
patients with superficial adenocarcinoma, low-grade dysplasia, and
metaplasia, in addition to 86 patients with high-grade dysplasia.

The major side-effects of PHOTOFRIN PDT were acute events related to the
light treatment, longer lasting effects relating to the healing of the
esophagus, and the extended period of photosensitivity of the skin.

-   The [acute]{.underline} effects were chest pain (in 47% of
    patients), abdominal pain (in 10%), fever (in 22%), nausea (in 39%),
    vomiting (in 34%), odynophagia (in 15%), and dysphagia (in 24%).
    Acute symptoms abated gradually, generally over about 4 weeks.

-   [Skin photosensitivity]{.underline} reactions were common (in 44% of
    patients), in spite of detailed warnings about exposure to sunlight
    and bright lights for 30 days. Most of the photosensitivity
    reactions occurred within 90 days after PHOTOFRIN injection. Most
    were mild (68%) or moderate (26%). Severe reactions (6%) were
    characterized by swelling, erythema, blisters, itching, burning
    sensation, and heat. All resolved over time.

-   The most important sub-acute effects were [esophageal
    strictures]{.underline}. Their treatment required repeated
    dilations, because PHOTOFRIN PDT injury results in deep (up to 6 mm)
    tissue necrosis, involving not only the esophageal mucosa but also
    the muscularis, and healing results in tight bands of fibrous
    tissue.

> The incidence of esophageal strictures depends on whether the data
> were collected from adverse event reports or from endoscopy reports.
> According to adverse event reports, symptoms of strictures occurred in
> 29.9% of patients. Endoscopy data were first collected using the term
> "esophageal stricture" regardless of subsequent management. Later on,
> only esophageal narrowing that required dilation was considered a
> stricture (incidence of 38.1%).
>
> Reviewer's Table 9 shows the incidence of strictures in the three
> trials, according to endoscopy data. Most of the strictures were noted
> after the first PDT course in the TCSC 96-01 trial, and after the
> second course in PHO BAR 01 (randomized) trial. In the randomized
> trial two patients had baseline strictures in the PHOTOFRIN PDT + OM
> arm and two patients, in the OM Only arm.
>
> **[Reviewer's Table 9. Esophageal Strictures Following PHOTOFRIN
> Photodynamic Therapy in PHO BAR 01, TCSC 93-07, and TCSC 96-01
> Patients (Endoscopy Data)]{.underline}**

+--------------------+----------+----------+-------------+-----------+
|                    | **TCSC   | **TCSC   | **PHO BAR   | **Total   |
|                    | 93-07**  | 96-01**  | 01**        | (%)**     |
+--------------------+----------+----------+-------------+-----------+
| **Numbers of       | **99**   | **86**   | **133**     | **318**   |
| patients in        |          |          |             |           |
| trial**            |          |          |             |           |
|                    |          |          |             |           |
| **(Safety          |          |          |             |           |
| populations)**     |          |          |             |           |
+--------------------+----------+----------+-------------+-----------+
| **Patients with    | **42     | **31     | **48        | **121     |
| strictures         | (        | (        | (36.1%)**   | (38.1%)** |
| following          | 42.4%)** | 36.0%)** |             |           |
| treatment**        |          |          |             |           |
+--------------------+----------+----------+-------------+-----------+
| **Course 1**       |          | **26     | **18        |           |
|                    |          | (        | (13%)**     |           |
| **Course 2**       |          | 30.2%)** |             |           |
|                    |          |          | **29        |           |
| **Course 3**       |          | **5      | (21%)**     |           |
|                    |          | (5.8%)** |             |           |
|                    |          |          | **1 (1%)**  |           |
|                    |          | **0**    |             |           |
+--------------------+----------+----------+-------------+-----------+

> There is no known method to prevent strictures at the present time.
> TCSC 96-01 trial tested the hypothesis that post-PDT corticosteroids
> may decrease the incidence of strictures, and randomized patients to
> receive corticosteroids or placebo. Treatment with corticosteroids did
> not reduce the incidence of strictures. Recent analyses suggest that
> areas of esophagus, which had received overlapping light exposure or
> had been treated a second time, appear to be predisposed to stricture
> formation (44% of such patients developed strictures compared to 24%
> of patients who did not have a mucosal segment treated twice).
>
> The only treatment for strictures at present is esophageal dilation.
> Patients with baseline strictures in the OM Only arm needed only one
> dilation. Most of the PDT-treated patients underwent multiple
> dilations, as shown in Reviewer's Table 10. The Sponsor characterized
> PHOTOFRIN PDT-related strictures as mild in 51.4% of patients,
> moderate in 38.8%, and severe in 9.7%. The data on esophageal
> dilations suggest that strictures require considerable medical
> attention and some risk. About 65% of patients with strictures
> required more than 2 dilations, about 36% required more than 5
> dilations, and about 15% required more than 10 dilations.
>
> **[Reviewer's Table 10. Esophageal Dilations in Patients with
> Treatment-related Strictures]{.underline}**

+-------------+-------------+-------------+-------------+-------------+
|             | **TCSC      | **TCSC      | **PHO BAR   | **Total**   |
|             | 93-07**     | 96-01**     | 01**        |             |
|             |             |             |             | **N = 318** |
|             | **N = 99**  | **N = 86**  | **N = 133** |             |
+-------------+-------------+-------------+-------------+-------------+
| **Number of | **42**      | **31**      | **48**      | **121**     |
| patients    |             |             |             |             |
| with        |             |             |             |             |
| s           |             |             |             |             |
| trictures** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **1 --2     | **12        | **14        | **16        | **42        |
| dilations** | (28.6%)\*** | (45.2%)\*** | (33.3%)\*** | (34.7%)\*** |
+-------------+-------------+-------------+-------------+-------------+
| **3 -- 5    | **13        | **12        | **10        | **35        |
| dilations** | (31.0%)\*** | (38.7%)\*** | (20.8%)\*** | (28.9%)\*** |
+-------------+-------------+-------------+-------------+-------------+
| **6 -- 10   | **7         | **5         | **14        | **26        |
| dilations** | (16.7%)\*** | (16.1%)\*** | (29.2%)\*** | (21.5%)\*** |
+-------------+-------------+-------------+-------------+-------------+
| **\>10      | **10        | **0**       | **8         | **18        |
| dilations** | (23.8%)\*** |             | (16.7%)\*** | (14.9%)\*** |
+-------------+-------------+-------------+-------------+-------------+

> **\*Percentage of the number of patients with strictures.**

Other safety indicators were the following:

-   There were six deaths in the three studies. None were related to
    treatment.

-   Serious adverse events were reported by 25% of patients treated by
    PHOTOFRIN PDT. Most common treatment-related SAEs were reported as
    gastrointestinal disorders and dehydration.

-   Adverse events that led to patient withdrawal from the studies
    included two patients who had esophageal perforations, one after
    esophageal dilation, the other after Nd:YAG laser treatment. One of
    these two patients underwent esophagectomy. One patient developed an
    anxiety reaction after PHOTOFRIN injection and before laser light
    treatment. Two patients had strokes, two were diagnosed with lung
    cancer, and one had worsening heart disease.

12. Ethical Standards and Financial Disclosure

-   The clinical trials were conducted in accordance with accepted
    ethical standards, including reviews of the protocols by
    Institutional Review Boards or Independent Ethics committees, and
    compliance with the Declaration of Helsinki, recommendations of the
    World Health Organization, Health Protection Branch (Canada), and
    the FDA, and with applicable state laws. Each patient reviewed and
    signed a written approved informed consent.

-   Three investigators admitted a proprietary or financial interest in
    the test product:

-   Masoud Panjehpour, Ph.D. indicated that he is a co-inventor of
    esophageal PDT balloon owned by Thompson Cancer Survival Center.

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-   Bergein F. Overholt, M.D. indicated that he is a co-inventor and
    co-patent holder for esophageal centering balloon.

-   Thomas J. Dougherty, Ph.D. indicated that he is a "co-inventor of
    PHOTOFRIN patent".

All the other investigators denied any financial interests or
arrangements. The Financial Disclosure Form is adequate.

13. Summary and Conclusions

-   PHOTOFRIN PDT appears to be an effective method of cancer risk
    reduction. The following findings lend support to this
    possibility: 1) cancer developed at about one-half the rate in the
    PHOTOFRIN PDT group as compared to the rate in the surveillance
    group, 2) PHOTOFRIN PDT was very effective in ablating HGD and
    leading to a Complete Response, and 3) patients with a Complete
    Response had a much lower probability of development of cancer than
    patients who failed to achieve a Complete Response. However, it is
    not possible to assess the long-term effectiveness of PHOTOFRIN PDT
    in cancer risk reduction using 2-year follow-up results. The Sponsor
    is continuing to follow PHO BAR 01 patients in PHO BAR 02 study that
    is expected to last 3 years.

-   PHOTOFRIN PDT was relatively well-tolerated, since very few patients
    left the trials because of treatment-related adverse effects.
    Nevertheless, the benefit/risk ratio is difficult to evaluate
    because long-term effectiveness in cancer risk reduction is not
    known at this time.

-   There was no esophagectomy arm in the Sponsor's studies, and
    patients who chose to undergo esophagectomy were not followed in any
    of the three studies. Thus, the efficacy (in cancer risk reduction)
    and safety of PHOTOFRIN PDT could not be compared to that of
    esophagectomy.

-   A surveillance program for patients with Barrett's Esophagus and HGD
    was an ineffective option for most patients. Over a follow-up period
    of at least 2 years, 84% of patients either developed cancer, chose
    an active form of treatment, or left the trial because of adverse
    events and administrative dismissals.

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-   HGD in Barrett's Esophagus is the only known lesion that progresses
    to adenocarcinoma of the esophagus. Even though 94% to 98% of
    esophageal adenocarcinomas are diagnosed in patients without a prior
    diagnosis of Barrett's esophagus, ablation of HGD offers a method of
    reducing the risk of this highly lethal disease in this select group
    of patients.

> **A P P E N D I X**
>
> Reviewer's Tables 5 and 6 for ITT populations.

**[Reviewer's Table 5. Progression to Cancer Among Responders and
Non-Responders in the Intent-to-Treat Populations with a Minimum
Follow-up of 24 Months]{.underline}**

+----------------------+-----------------------+-----------------------+
| **Patient group**    | **Total number of     | **Total number who    |
|                      | patients**            | progressed to         |
|                      |                       | cancer**              |
+----------------------+-----------------------+-----------------------+
| **PHOTOFRIN PDT**    | **138**               | **18 (13.0%)**        |
|                      |                       |                       |
| -   **CR1+CR2+CR3**  | **106**               | **6 (5.7%)**          |
|                      |                       |                       |
| ```{=html}           | **32**                | **12 (37.5%)**        |
| <!-- -->             |                       |                       |
| ```                  |                       |                       |
| -   **No response**  |                       |                       |
+----------------------+-----------------------+-----------------------+
| **OM Only**          | **70**                | **20 (28.6%)**        |
|                      |                       |                       |
| -   **CR1+CR2+CR3**  | **27**                | **1 (3.7%)**          |
|                      |                       |                       |
| -   **No response**  | **43**                | **19 (44.2%)**        |
+----------------------+-----------------------+-----------------------+

**[Reviewer's Table 6. Relative Frequencies of Responses in ITT
Populations]{.underline}**

+--------------+--------------------+------------------+---------------+
| **Quality of | **PHOTOFRIN PDT +  | **OM Only**      | **Fisher's    |
| response**   | OM, N = 138**      |                  | exact**       |
|              |                    | **N = 70**       |               |
|              |                    |                  | **P value**   |
+--------------+--------------------+------------------+---------------+
| **CR1**      | **72 (52.2%)**     | **5 (7.1%)**     | **\<0.0001**  |
+--------------+--------------------+------------------+---------------+
| **CR2**      | **9 (6.5%)**       | **5 (7.1%)**     | **1.000**     |
+--------------+--------------------+------------------+---------------+
| **CR3**      | **25 (18.1%)**     | **17 (24.3%)**   | **0.3609**    |
+--------------+--------------------+------------------+---------------+
| **No         | **32 (23.2%)**     | **43 (61.4%)**   | **\<0.0001**  |
| response**   |                    |                  |               |
+--------------+--------------------+------------------+---------------+

**ATTACHMENT TWO**

**MEDICAL DEVICE REVIEWER'S SUMMARY**

May 22, 2003

Briefing document for devices for use with Photofrin in the treatment of
Barrett's Esophagus.

There are three specific devices that are used in combination to deliver
the required optical radiation to the treatment site for the activation
of the drug Photofrin for the treatment of high- grade dysplasia in
Barrett's Esophagus. The devices that make up this total system are:

1.  The Diomed 630 PDT Laser Model T2USA is a diode laser with an output
    wavelength of 630 ± 3 nm which has been shown in past studies to be
    effective in the activation of the drug Photofrin. The Diomed 630
    PDT Laser is capable of delivering 2000 mW of laser energy at the
    delivery fiber tip. This laser system has been shown to be
    compatible with the OPTIGUIDE Diffusing Fiber Optics used in this
    study as the light delivery systems. When using the Diomed laser to
    activate Photofrin for treatment of Barrett's Esophagus, the
    physician will specify the diffuser length to be used in the
    treatment and the laser software will calculate the laser on time to
    produce the required 130 J/cm of diffuser length required for
    treatment. The package insert for the OPTIGUIDE Diffusing Fiber
    Optics contains specific tables for each diffuser length,
    corresponding laser setting and required on time for the required
    fluence for treatment.

2.  The OPTIGUIDE Fiber Optic Diffusers, like the Diomed 630 PDT Laser
    have been shown in previous studies to be capable of delivering the
    required 630 nm light to target sites for the activation of
    Photofrin. These diffusing fibers are used in the treatment of
    Barrett's Esophagus in two different methods. Diffusing fibers of
    1.0 to 2.5 cm are used to either pretreat nodular areas prior to
    treatment of the total dysplastic area or can be used following
    treatment at follow-up to treat skipped areas. The second use for
    these diffusing fibers is to deliver the required activating light
    to the Wizard Balloon Diffuser for the treatment of the total
    dysplastic area of Barrett's. Fibers having lengths of 5.0, 7.0, and
    9.0 cm are used with the corresponding window size of Wizard
    Balloon. The OPTIGUIDE diffusers are designed to allow exposure of
    tissue in a circumferential pattern 90^o^ to the fiber shaft in a
    360^o^ pattern with no forward or reverse exposure. The package
    insert for the fibers comes with tables for each length of fiber and
    required laser output in mW and recommended time for treatment.

3.  For the actual treatment of the dysplastic Barrett's area, a third
    device is required. This device is the Wizard X-Cell which is a
    combination device consisting of a balloon with a 360^o^ window for
    total exposure of the intended treatment site. As with the OPTIGUIDE
    diffusers, the Wizard X-Cell incorporates reflective mirrors to
    prevent both forward or reverse exposure with the added advantaged
    that this internally reflected light enhances the light energy
    available for treatment. The actual treatment light is delivered
    through the windows by use of the appropriate length OPTIGUIDE Fiber
    Optic Diffuser. In actual use the diffuser used to deliver the light
    to the Wizard is longer than the Wizard window to insure total
    exposure. The Wizard windows are 3, 5, and 7 cm in length thus the
    corresponding diffuser length would be 5, 7, and 9 cm. The balloon
    feature of the Wizard X-Cell provides some stability to device
    positioning and also provides some smoothing of the esophageal folds
    to allow for a more uniform light exposure.