FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

MEETING OF THE

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

8:07 a.m.

Wednesday, September 10, 2003

Holiday Inn

Montgomery Village Avenue

Gaithersburg, Maryland

ATTENDEES

COMMITTEE MEMBERS:

ROBERT S. STERN, M.D., Acting Chairman

Professor of Dermatology

Beth Israel Deaconess Medical Center

330 Brookline Avenue

Boston, Massachusetts 02215

KIMBERLY LITTLETON TOPPER, M.S.

Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane, HFD-21

Rockville, Maryland 20857

ROBERT KATZ, M.D.

Dermatology Clinic

11510 Old Georgetown Road

Rockville, Maryland 20852

PAULA KNUDSON, Consumer Representative

Executive Coordinator of IRB Research and

Academic Affairs

The University of Texas

Houston Health Science Center

1133 John Freeman Boulevard

Jesse Johnes Library, Room 322

Houston, Texas 77030

SHARON S. RAIMER, M.D.

Professor and Chairman

Department of Dermatology

University of Texas Medical Branch

Galveston, Texas 77550-0783

KATHLEEN Y. SAWADA, M.D.

Dermatologist

Alpine Dermatology Associates P-LLC

1785 Kipling Street

Lakewood, Colorado 80215

ATTENDEES (Continued)

CONSULTANTS: (voting)

MICHAEL BIGBY, M.D.

Department of Dermatology

Beth Israel Deaconess Medical Center

330 Brookline Avenue

Boston, Massachusetts 02215

LYNN A. DRAKE, M.D.

Massachusetts General Hospital

Dermatology, Bar 604

40 Blossom Street

Boston, Massachusetts 02114-2696

LLOYD E. KING, JR., M.D., Ph.D.

Professor of Medicine, Dermatology Division

Vanderbilt University

1301 22nd Avenue North

3900 TVC (The Vanderbilt Clinic)

Nashville, Tennessee 37232-5227

EILEEN RINGEL, M.D.

325-C Kennedy Memorial Drive

Waterville, Maine 04901

JIMMY D. SCHMIDT, M.D.

819 Peakwood

Houston, Texas 77090

MING T. TAN, Ph.D.

University of Maryland

Department of Epidemiology and Preventative Medicine

Division of Biostatistics

22 S. Greene Street, N9E17

John Eager Howard Hall, Room 109

Baltimore, Maryland 21201

THOMAS R. TEN HAVE, Ph.D.

Department of Biostatistics and Clinical Epidemiology

University of Pennsylvania

School of Medicine

607 Blockley Hall

423 Guardian Drive

Philadelphia, Pennsylvania 19104-6021

ATTENDEES (Continued)

ACTING INDUSTRY REPRESENTATIVE: (non-voting)

R. TODD PLOTT, M.D.

Vice President

Clinical Research and Regulatory Affairs

Medicis Pharmaceutical Company

8125 N. Hayden Road

Scottsdale, Arizona 85258

GUEST SPEAKERS: (non-voting)

STEVEN M. ROTTER, M.D.

77700 Leesburg Pike

Suite 5423

Falls Church, Virginia

FOOD AND DRUG ADMINISTRATION STAFF:

MOHAMED ALOSH, Ph.D.

Biostatistics Team Leader

Division of Biometrics III

Office of Biostatistics/OPaSS

Center for Drug Evaluation and Research

JONCA BULL, M.D.

Director

Office of Drug Evaluation V

Center for Drug Evaluation and Research

MARKHAM C. LUKE, M.D., Ph.D.

Dermatology Team Leader

Division of Dermatologic and Dental Drug Products

Office of Drug Evaluation V

Center for Drug Evaluation and Research

BRENDA VAUGHAN, M.D.

Medical Officer

Division of Dermatologic and Dental Drug Products

Office of Drug Evaluation V

Center for Drug Evaluation and Research

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF: (Continued)

JONATHAN WILKIN, M.D.

Division Director

Division of Dermatologic and Dental Drug Products

Office of Drug Evaluation V

Center for Drug Evaluation and Research

PHOTOCURE ASA REPRESENTATIVES:

LASSE BRAATHEN, M.D., M.H.A.

WILLIAM CLEMENTI, PHARM.D., F.C.P.

PER FUGLERUD, PH.D.

VIDAR HANSSON, M.D., PH.D.

KJETIL HESTDAL, M.D., PH.D.

HILDE MORRIS, D.V.M.

DEDEE F. MURELL, M.D., FAAD

DAVID M. PARISER, M.D., FACP

JOHN POSNER, M.D., PH.D., FRCP

C O N T E N T S

NDA 21-576, Methyl Aminolevulinate Hydrochloride,

(Methyl aminolevulinate cream, 168mg/g)

by PhotoCure ASA

\- - -

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Ms. Kimberly Topper 10

INTRODUCTION

by Dr. Jonathan Wilkin 21

PHOTOCURE ASA PRESENTATION

Introduction

by Dr. Vidar Hansson 23

Regulatory Overview

by Dr. William Clementi 27

Overview of Clinical Development Program

of MAL-PDT in BCC

by Dr. Kjetil Hestdal 28

Efficacy in BCC: Placebo-controlled Studies

by Dr. David Pariser 34

Efficacy in BCC: Active-controlled Studies

by Dr. David Pariser 44

Efficacy in High-risk BCC,

Including Long-term Follow-up

by Dr. Dedee Murrell 50

Safety, Including Skin Sensitization

by Dr. John Posner 58

MAL-PDT in BCC Benefit/Risk

by Dr. Kjetil Hestdal 73

COMMITTEE DISCUSSION 74

C O N T E N T S (Continued)

AGENDA ITEM PAGE

FDA PRESENTATION

by Dr. Brenda Vaughan 81

by Dr. Mohamed Alosh 86

COMMITTEE DISCUSSION 110

OPEN PUBLIC HEARING 146

COLD STEEL SURGERY AND MOHS MICROGRAPHIC

SURGERY AND THEIR EFFICACY FOR NODULAR

BASAL CELL CARCINOMA

by Dr. Steven Rotter 146

COMMITTEE DISCUSSION 161

QUESTIONS 200

P R O C E E D I N G S

(8:07 a.m.)

DR. STERN: Good morning, everyone. This is the Dermatologic and
Ophthalmic Drugs Advisory Committee to consider materials related to NDA
21-576, methyl aminolevulinate hydrochloride phototherapy. I\'d like to
ask permission to call this MAL-PDT so I don\'t have the same problems I
had yesterday with pronunciation.

(Laughter.)

DR. STERN: So if it\'s okay with the sponsors, we\'ll refer to this as
MAL-PDT, MAL standing for the word I just said, and PDT standing for
photodynamic therapy, since we\'re considering both a chemical and a
physical modality of therapy together. So if there are no objections,
anyone can call it by the long name, but that is what I\'ll do.

So let\'s begin this morning by going around the table and everyone
introducing themselves. I\'m Rob Stern. I\'m the chairman of the
committee today and am from Boston at the Beth Israel Deaconess Medical
Center and Harvard Medical School, and I\'m a dermatologist by training.

DR. PLOTT: My name is Todd Plott. I\'m Vice President, Clinical Research
and Regulatory Affairs at Medicis. I\'m the industry representative.

DR. RINGEL: I\'m Eileen Ringel. I\'m a dermatologist. I\'m in private
practice in Waterville, Maine.

DR. TAN: I\'m Ming Tan, Professor of Biostatistics at the University of
Maryland School of Medicine, Department of Preventive Medicine and
Epidemiology.

MS. KNUDSON: I\'m Paula Knudson, the consumer representative, and I am
an IRB chairperson and administrator at the University of Texas Health
Science Center, Houston.

DR. DRAKE: I\'m Lynn Drake. I\'m a dermatologist on the faculty at
Harvard and I\'m based at the Massachusetts General Hospital.

DR. BIGBY: I\'m Michael Bigby, yet another dermatologist from Boston.

DR. KING: I\'m Lloyd King. I\'m a dermatologist from Vanderbilt
University in Nashville, Tennessee.

MS. KNUDSON: I\'m Robert Katz. I\'m a dermatologist in Rockville,
Maryland, consultant in dermatology at Walter Reed Army Medical Center.

DR. SAWADA: I\'m Kathleen Sawada, private practice, Lakewood, Colorado,
dermatologist.

MS. TOPPER: Kimberly Topper. I\'m the executive secretary for the
committee.

DR. RAIMER: I\'m Sharon Raimer, dermatologist, University of Texas in
Galveston, Texas.

DR. TEN HAVE: Tom Ten Have, biostatistics and epidemiology, University
of Pennsylvania.

DR. SCHMIDT: I\'m Jimmy Schmidt from Houston, Texas in private practice.

DR. VAUGHAN: I\'m Brenda Vaughan, dermatologist, FDA, medical officer.

DR. LUKE: Markham Luke. I\'m a dermatologist. I\'m the clinical team
leader at FDA.

DR. WILKIN: Jonathan Wilkin, Director of the Division of Dermatologic
and Dental Drug Products, FDA.

DR. BULL: Good morning. Jonca Bull, Office Director, Office of Drug
Evaluation V.

DR. STERN: We\'ll now move on to the conflict of interest statement.

MS. TOPPER: The following announcement addresses the issue of conflict
of interest with regard to this meeting and is made a part of the record
to preclude even the appearance of such at the meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by committee participants, it has been determined
that all interests in firms regulated by the Center for Drug Evaluation
and Research present no potential for an appearance of a conflict of
interest at this meeting.

We would also like to note that Dr. R. Todd Plott has been invited to
participate as a non-voting industry representative, acting on behalf of
regulated industry. He is Vice President of Clinical Research at Medicis
Pharmaceutical Company.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from involvement and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
in any firm whose products they may wish to comment upon.

Thank you very much.

DR. STERN: I\'d like to take a few moments to do two things. I thought,
in thinking about this product where the indication is for the treatment
of basal cell carcinoma, it might be good, particularly for the
non-dermatologists, to have a little context at least as to how I see
basal cell carcinoma and talk a little bit about currently available
treatments for this tumor.

So basal cell carcinoma has a very high incidence in the United States.
There are probably between three-quarters of a million and 1 million new
and recurrent tumors a year. A slight majority occur on the face and
neck and a substantial majority in sun-exposed areas, if one includes
the forearms and the distal legs.

The diagnosis, at least in my hands, is not always easy without
histology. There are a number of lesions that I sometimes mistake for
them. So many of us think it\'s always good to not be surprised and not
do destructive things without knowing what you\'re treating.

They generally do not metastasize, but both primary tumors and
recurrences can be very problematic with respect to substantial
morbidity, although very low mortality, particularly when they occur on
the head and neck where there can be substantial disfigurement, and with
recurrent tumors, not rarely, interference with vital functions such as
eyes.

The response to therapy varies with type, size, and location.

So from someone who has been treating these tumors for just over 30
years now and does mainly non-surgical treatment almost exclusively and
refers on surgical treatment, the attributes of a desirable treatment
for basal cell carcinoma from a patient\'s perspective is that it\'s
quick ‑‑ and \"quick\" means low number of visits as well as low time at
the visit ‑‑ painless, quick healing, limited wound care restrictions.
You can go out and play golf that afternoon, or at least two days later.
Good cosmetic result, and that the tumor is unlikely to recur and need
additional treatment.

The characteristics of a therapy from a physician\'s point of view that,
in addition to meeting the patient\'s needs, maximize its usefulness in
clinical practice, are simple. The therapy can standardize to limit
interoperator variability. You know that no matter who does it, you\'re
going to get a good result, that appropriate lesions can be easily
identified. We spend a lot of time teaching residents that for this
lesion in this location, you want to do this, but if there is this going
on, you want to do that. So you want to have it so you know for any
therapy what are in fact indications and counterindications and what
among the alternatives put it at the top of the list, hence the choice
for the individual patient.

That there is a very high response rate and that recurrences not only be
infrequent, but one thing is, at least in my clinical experience,
recurrences at the edge, particularly of superficial basal cells have a
lot less associated morbidity than deep recurrences, which often take
awhile to manifest themselves clinically, so often can grow large and
involve deeper structures before, in fact, they\'re detected clinically.

So current therapies ‑‑ and I\'ll talk a little bit more about these in
a second ‑‑ are electrodesiccation, curettage, cryosurgery, excisional
surgery, Mohs surgery. I\'ve left out topical chemotherapy with 5-FU and
a whole variety of other less frequently used therapies. The sponsors
are from a radium institute. I\'ve left out radiation therapy, but I
would say of the primary and recurrent tumors treated in dermatologic
practice, well over 90 percent are treated by these four modalities,
probably more than 95 percent. So these are the main things in terms of
common practice that we talk about.

So questions for the committee about the product is, is there sufficient
data for us to know how well it works? Is the therapy sufficiently
clear; that is, clear in terms of indications and how to use it to be
used effectively? And some questions I have that I hope we\'ll address
is why did the results vary so greatly center to center in the study.
And a question that is not for approval but as a clinician I only ask
myself, does it work well enough to be a meaningful addition. The C was
supposed to come out of there.

(Laughter.)

DR. STERN: I know you\'re hoping it would be an \"addiction\" in
clinical practice.

(Laughter.)

DR. STERN: But a meaningful addition given our available therapies.

I talked to someone within the agency and we had a discussion about so
what really are recurrence rates and wouldn\'t it be nice to sort of
review for the committee the literature on recurrence rates.
Fortunately, I have working with me a fifth-year Harvard medical student
who is substantially more intelligent and higher energy than I am. Jean
Lee was willing to prepare this presentation and review the literature
with very little notice and, from my perspective, did an excellent job.
So I\'m presenting the materials here. These are articles I\'ve all read
at one time but not recently. I just went over the key data tables, but
knowing Jean Lee, I think you\'ll agree this is an accurate
representation, or I hope you\'ll agree.

So current modalities. Surgical excision is usually reserved for small,
well-defined tumors on low-risk areas performed with 4 to 5 millimeter
margins typically, although there\'s a huge variation in the application
of surgery depending on the skill of the operator, the availability of
frozen sections, a whole variety of things. But one would say those are
some of the clear indications.

Cryosurgery is usually reserved for small tumors on cosmetically less
sensitive areas because of frequent depigmentation and macular scars at
the sites of treatment.

Curettage and electrodesiccation. Usually for low-risk trunk and
particularly for lower extremity lesions where it\'s often very
desirable because you don\'t have to graft when you can\'t do, in fact,
the primary closure on lesions.

Mohs micrographic surgery is used for high-risk tumors, used on the
faced, basically a way for tissue preservation and almost certainly a
lower risk of recurrence, and used in recurrent tumors where the anatomy
has been changed so the usual landmarks by which we judge surgical or
destructive therapies are absent and we need something to actually guide
ourselves microscopically in looking at the individual case as opposed
to applying guidelines.

So what are the predictors of basal cell recurrence? Size of tumor.
Larger tumors recur more frequently. Clinically indistinct margins are
more likely to be associated with recurrence. Location, particularly on
the embryonic fusion plates which provide little resistance to tumor
growth, particularly in the central face. Histologic type. It\'s a lot
easier to cure nodular and superficial basal cells than it is sclerosing
and morpheaform or mixed types. Perineural invasion tumors, again mainly
on the face, are more likely to recur. Recurrent tumors are more likely
to recur again. If it was nasty the first time, although it\'s no
guarantee of future behavior, the best prediction of future behavior is
past behavior for these tumors, as well as many things in life.
Previously irradiated tumors with X irradiation seem to have a high
recurrence rate. And probably most important, after you standardize for
all of these modalities, is the skill of the operator.

So the problem is what do you mean by a recurrence rate. We tried to
look at three different kinds of recurrence rates. One is a raw
recurrence rate, which is the total number of recurrences divided by the
total number of tumors treated. A strict recurrence rate is the total
number of patients with recurrence divided by the number of treated
patients observed for at least 5 years. So if a person had three tumors
treated and one recurred, they would be counted as a recurrent case
since the modality failed in one of these tumors.

And the second and the way that, as far as I can tell, is almost never
given in the label and the most appropriate, is a life table cumulative
recurrence rate which adjusts for the rates according to the number of
persons in each year of follow-up. But if you can find good life table
studies of recurrence rates, please let me know.

So in the bolder, non-italicized type are in fact direct data on all of
the following slides taken directly from the Thissen review, a
systematic review of treatment modalities, which was published in the
Archives of Dermatology about four years ago. In each of the slides, the
ones in italics are basically what Jean Lee did in abstracting from
other literature we found that was not cited primarily in the systematic
review published four years ago.

Here we have for basal cell cancer for Mohs surgery, and you can see
basically that recurrence rates, at least in the literature, range from
.5 percent to about 2 percent in terms of these. There\'s one outlier,
the Lundgren study, but in fact these were very high-risk sites and some
sites are more likely to recur. I think many people accept the 1 to 2
percent recurrence rate, which will clearly vary substantially
particularly with the operator\'s skill and with the location and type
of tumors that the individual operator is operating on.

Surgical excision. Again, the same caveats about data sources here. The
rates that you can see, in terms of cumulative recurrence rates, range
in the 2 to 10 percent area at 5 years. Let me bring some attention to,
again, how much rates will vary. Even looking in the Spraul study of
2000, which is about six down, looking at very difficult periocular
tumors where people try to get as small of margins as possible, with
negative margins by histology at the time of excision, there was 2.3
percent recurrence, and of those tumors that had positive margins, there
was a 12 percent recurrence rate. I think in looking at these data, most
people would say it\'s about 5 and could be as high as 10 percent with a
recurrence rate at 5 years.

Cryosurgery. Again, what you\'re doing and where you\'re doing it, size
of lesions is evident here. If you look at, again, the eyelid which is
particularly difficult to treat with large lesions, larger than usually
recommended, certainly on the face with cryosurgery, a 16 percent
recurrence rate at 5 years, but in fact for the other studies basically
a 2 to 6 percent recurrence rate.

Electrodesiccation and curettage. Here we have similar to slightly
higher recurrence rates as reported for cryosurgery. However, often
smaller tumors are treated with cryosurgery more frequently, superficial
basal cells. So you may have easier-to-treat tumors in the first case.
Again, here you can see a range of estimates, and I think the most
interesting one is the Dubin and Kopf study where he showed that if you
look at trainees, you get a high recurrence rate, and in fact they
showed in their own practices by board certified dermatologists a rate
about one-fifth as high. So if you don\'t know what you\'re doing with
this, you probably shouldn\'t be doing it. If you know what you\'re
doing, you can expect a recurrence rate for most kinds of tumors in the
3 to 6 percent range at 5 years.

So, in summary, the range of recurrence rates appears to be relatively
similar for most physical modalities, including surgical excision,
cryosurgery, electrodesiccation and curettage, curettage and
electrosurgery, and curettage alone, although the data elements for the
last two are sufficiently small that I didn\'t put them up. They\'re
basically single-operator kind of limited studies, and that is excluding
Mohs.

For a follow-up period of 3 to 4 years, this rate falls between 3 to 5
percent. For 5 years and more, the rate approximately doubles to 5 to 12
percent. Recurrence rates for Mohs are probably lower, probably within
the 1 to 2 percent range.

So, in conclusion, the key predictors of tumor recurrence are size, site
of location, histology, and skill of the operator. All of the non-Mohs
modalities have roughly equal and excellent cure rates for basal cell
carcinoma. Of those that are treated with high-risk characteristics,
there\'s an increased risk of basal cell recurrence regardless of
treatment modality with increasing time. This underscores the importance
of looking at data and adjusting for time and long follow-up time for
evaluating the effectiveness of therapy.

Thank you.

Dr. Wilkin?

DR. WILKIN: I can say a few words. From time to time, FDA as a
scientific regulatory agency needs access to highly qualified expert
advisors who can speak to the clinical science and also to the values,
the values in clinical judgment, societal values, that relate to
standards of care.

The topics which may come before an advisory committee such as this
include new products, that is, products that are new in a line.
PhotoCure has submitted an application for methyl aminolevulinate with
photodynamic therapy for nodular and superficial basal cell carcinoma,
and that would constitute a new product and a new line. So it\'s a
reasonable topic for this committee to think about.

PhotoCure will begin the analysis of the data this morning. They will
lay everything out, and then FDA will speak after that and comment on
some aspects of our analysis that might be somewhat different, but it\'s
another way of looking at the issues.

Then we were seeking expertise, dermatologic surgical expertise. We
actually contacted over a dozen dermatologic surgeons and only one is
able to join us and not until this afternoon. So I did contact Dr. Stern
last week and alerted him to that, and I think it was a very helpful
overview that we just heard because I think that may enter into the
discussions among committee members what is already out there for
nodular basal cell carcinoma and how this product may fit into the
overall armamentarium.

Along with that, I would encourage the members of the committee to think
about the potential tools we have in labeling. When I say labeling, I\'m
talking as an FDAer. It\'s what most people call package inserts. There
is a portion of the Code of Federal Regulations, 201.57, that sort of
outlines how we think about labeling. It gives us, for example, the
order in which things show up in labeling, its the description section,
and then clinical pharmacology. The third section is the indication
section. In the indication section, there is the potential for
elaboration to define the population that is most appropriate for a
particular drug product.

Also, some other sorts of information can be added into that section
that would be helpful to a clinician. Dr. Drake is with us today, and we
have known from previous advisory committees that she\'s very helpful in
crafting wording which is supportive, informative, but doesn\'t box
clinicians in. I think that\'s basically the key piece. So I think we
would like to hear that also from the committee, when you are answering
the different questions, if you can think about labeling options that
may be helpful to the practitioner.

And then something that\'s not on the agenda but will no doubt be
observed today, because this is the last day of the meeting of this
advisory committee this week, possibly around 11:30 or noon, you\'ll
start seeing luggage pile up on the wall. I would just say to the new
members of the advisory committee that this committee has a tradition,
under Dr. Stern and his predecessor, Dr. Drake, as chair, that the
committee has stayed until everything has been thoroughly discussed. So
I\'m happy to say that we\'ll be able to thank everyone at the end of
the day for making it through and giving us good advice.

DR. STERN: Thank you, Dr. Wilkin.

We\'ll next go on to the presentation by PhotoCure of the MAL-PDT
application.

DR. HANSSON: Dr. Wilkin, Mr. Chairman, members of the committee, ladies
and gentlemen. My name is Vidar Hansson. I\'m the President and CEO of
PhotoCure. I have a medical background from \'69 at the University of
Oslo. I have a Ph.D. primarily from research done in the United States
in Chapel Hill actually in molecular endocrinology and molecular cell
biology. My experience in the medical field is six years as an associate
professor in pathology and actually 21 years as a professor in
biochemistry and molecular cell biology. And for the last six years,
I\'ve been the CEO of PhotoCure.

I will just say a few words about the rationale for choosing MAL. I
agree with you. We will use MAL-PDT rather than the full name to make
things simpler for us.

We will have a regulatory overview by Dr. Clementi. Dr. Hestdal will
make a brief overview of our clinical program. Dr. Pariser will review
some of our important studies in what we call non-high-risk or low-risk
basal cell carcinoma, and Dr. Murrell will then review two of our
studies on what we call high-risk basal cell carcinoma. Of course,
safety will be addressed by Dr. Posner, and Dr. Hestdal will finally try
to sum up the benefit-risk ratio of this new treatment.

First, a few words about PhotoCure, which is a very new company. The
first employee was the 2nd of January 1997. It springs out from the
Research Institute at the Norwegian Radium Hospital, which is the
largest comprehensive cancer center in northern Europe. It has a
research institute of more than 200 full-time employees, and PhotoCure
is one of several scientific experiences and one of the two commercial
activities coming out from this institution.

This just lists some properties of methyl aminolevulinate. MAL actually
is an ester monocarbon substitution on the carboxy group of
aminolevulinic acid and, for reasons we only partly know, causes quite
dramatic changes in the biological properties of this molecule in the
rapid and efficient induction of intracellular porphyrins primarily in
cancer cells and almost not in normal cells, and for other reasons we
also only partly know, a very low ability to cross the basal membrane
and very low uptake into the body. Upon illumination with red light,
this induces photoactivation of the intracellular proteins and death of
the tumor cells but not the surrounding normal cells and by a process
that recent publication means comes through apoptosis.

This is just an example of MAL penetration into a small nodular lesion.
You can see the demarcation of the basal membrane here, some tumor, some
normal lamina propria, and normal tissue around. You see a freeze crack
here in the frozen section. You see a cystic clearance here which is
actually a central necrosis in the tumor that you frequently see in
nodular lesions.

The MAL cream was applied for 3 hours, and this is then a fluorescent
image in a CCD camera where you activate by blue light and do the red
fluorescence recording and you shoot the photographs.

This really shows the very low induction of photoactive porphyrins of
MAL cream compared to the parent compound, the aminolevulinic acid. If
you apply a cream containing MAL or ALA for 3 hours to the inside of the
underarm of a human being and you look at the fluorescence of
photoactive porphyrins after activation by blue light, with the MAL
cream you see little or no fluorescence, whereas with the parent
compound you actually see a very strong fluorescence even in the normal
skin.

For practical purposes, there\'s very high selectivity between the basal
cell carcinoma. Here you see a large basal cell carcinoma, 12
centimeters in diameter, on the shoulder of a human being. Here you go
into the dark room. You activate the porphyrins with blue light. You
record the red fluorescence. This is actually what you see with your
bare eyes. You can actually shoot the picture with an ordinary mirror
reflects camera, and you see how the fluorescence is really located and
demarcate the tumor and not in the surrounding normal tissue.

This cartoon actually tries to illustrate the mechanism by which MAL-PDT
works. You put on the cream for 3 hours and 8 molecules of MAL makes a
porphyrin, and then upon illumination with red light, makes reactive
oxygen species and primarily singlet oxygen that kills the cells.

This shows how this extreme lesion cell activity and penetration
throughout the lesion gives the possibility for successful tumor removal
and tissue conservation in a case as shown here. This dotted line
actually shows the tumor, and they started, of course, with Mohs
surgery. This was on anticoagulant therapy and because of excessive
bleeding, as well as problem with the anesthesia, they had to stop the
Mohs surgery and they had a small graft on the tip of the nose. When he
came back after a while, he was put into our high-risk study in
Australia, and at baseline and 3 months, he was in complete response. He
still has a sustained complete response verified 24 months after
treatment. I think this is just one example of how MAL-PDT can be used
in certain situations where surgery may not be appropriate.

I will then give it over to Dr. Clementi, our regulatory consultant and
U.S. agent. Please, Dr. Clementi.

DR. CLEMENTI: Thank you, Vidar.

Methyl aminolevulinate, or MAL-PDT, is not going to be the trade name
for this product. We are searching for a trade name, so we\'ll work with
MAL-PDT today.

It is a combination product, both a device and a cream, being reviewed.
The CureLight broadband model CureLight 01 has received an approvable
letter from CDRH and methyl aminolevulinate cream is the discussion that
we\'re entertaining today.

We followed a reasonably conservative regulatory path. We met with the
division many times. We have two applications with this division, one on
actinic keratosis and one on basal cell carcinoma. We\'re not talking
about actinic keratosis today, but many of the comments we received on
the chemistry and manufacturing controls and on the preclinical sciences
were applied to our development program in basal cell carcinoma. As you
can see, we met often. We filed our IND for AK in 2000. That was
preceded by our IND in December of 1999, and our NDA was filed in
February of 2003.

We did have a total of six major meetings with the division. We enjoyed
all of them. We found all of them productive, but we generated a lot of
questions in the process. So for AK we had our three traditional
meetings, and for basal cell carcinoma, we had our pre-IND meeting, our
end-of-phase II in March of 2000, and our pre-NDA meeting in June of
2002.

Thank you very much. I\'d like to turn the presentation over to my
colleague and friend, Dr. Hestdal.

DR. HESTDAL: Thank you. Chairman, ladies and gentlemen, I will go
through a summary of the clinical development. That will be discussed in
more depth in a later presentation.

My name is Kjetil Hestdal. I\'m the Vice President of Research and
Development at PhotoCure. I have a medical degree and have a Ph.D. in
basic immunology obtained at the National Cancer Institute here in
Bethesda.

The clinical development program assessed different aspects. Of course,
we had to identify optimal cream concentration, cream application time,
and the illumination parameters. This was established in phase I/II
studies.

The efficacy of MAL-PDT in BCC was demonstrated in two adequate and
well-controlled studies in primary nodular BCC using vehicle as the
control. Furthermore, we also have a study of the relative efficacy in
primary nodular and superficial BCC using surgery and cryotherapy as
comparators. We have obtained supportive evidence from two studies on
the efficacy and safety of MAL-PDT in nodular and superficial high-risk
BCC.

The safety profile that will be shown to you later is based on patients
from clinical trials both in BCC and AK, and in addition to that,
special safety studies.

If we go to the dosing parameters, the assessment of cream
concentration, cream application time, and light dose were assessed in
three different studies. It\'s important to say that in two of those
studies, we used the fluorescence ability of photoactive porphyrins to
establish the dose penetration and selectivity. In addition, we had a
phase II study that established the safety. So the cream concentration
comes from one study where we actually measured the photoactive
porphyrin fluorescence in the depth of the lesion using three different
concentrations of the cream.

The cream application time was done also measuring the fluorescence from
the photoactive porphyrins both in BCC as well as in the normal tissue
and established a selectivity during 28 hours of cream application.

Lesion penetration was also assessed in the same way as the cream
concentration using two different time points.

Clinical efficacy was then established examining the efficacy of the
four different time points of cream application.

The light dose. We also used the ability of the photoactive porphyrins
and the activation and we looked the photobleaching of this when you do
the illumination.

The conclusion of the dosing is that the highest penetration in the BCC
lesion was obtained in the highest concentration examined, 168
milligrams per gram. The application time was assessed based on the
optimal penetration, the highest time point for selectivity, and the
clinical efficacy turned out to be 3 hours. The light dose was
established when we obtained complete photobleaching using red light of
a wavelength of 570 to 670 nanometers and a total dose of 75 Joules per
square centimeter.

This is just a brief example of the method. It consists of a lesion
preparation using a curette, it has cream application, and then you have
illumination for 10 minutes.

DR. BIGBY: Are the patients anesthetized for the curettage step?

DR. HESTDAL: If you allow me, if it\'s okay with the chairman and you,
to take the question when we are finished the discussion, I think it
will be addressed by our clinical experts. Is that okay?

DR. STERN: Sure.

DR. HESTDAL: So the cream concentration was 160 milligrams per gram and
was applied in a 1 millimeter thick layer on the lesions and 5
millimeters on the surrounding skin. 3 hours under occlusive dressing of
the cream. The light dose, as I said, was 75 Joules using the red light.
Generally, two treatment sessions, 1 week apart, constituting one
treatment cycle, were used and the possibility of a second treatment
cycle 3 months later in case their lesion showed a non-complete
response.

This is a picture of the light that has been used in all clinical
studies, and the light is obtained from a halogen light bulb. The lens
system in the lamp head provides focus and homogeneous light. There are
also filters that remove blue light, UV, and infrared light and in this
way, with these filters provides a red light with a specific wavelength
between 570 and 670 nanometers. The light intensity has been 50 to 200
milliwatts per square centimeter and it\'s dependent on the distance
from the treatment site. Again, this lamp gives a circular treatment
area of 30 to 55 millimeters in diameter.

This lamp, as I said, has been used in all clinical studies except for 6
patients where a light source with similar physics was used. However,
that lamp had a bigger light field.

Throughout the whole program, we have tried to standardize the methods.
In regard to efficacy, we examined efficacy both on the patient level,
as well as on the lesion level. Patient means that a patient can have
several lesions. For the patient to be considered a complete response,
all lesions on that patient have to be in complete response. Then we
have assessed the lesion response on the individual lesions, and this is
done both clinically as well as in four studies with histological
verification using in the high-risk population a punch biopsy, while in
the two vehicle-controlled studies, we have used serial sectioning.

The recurrence has been assessed annually by clinical assessment of the
lesion site. Of course, we have assessed the cosmetic outcome both
judged by the investigator as well as the patient, and safety has been
obtained collecting local and non-local ‑‑ that means systemic ‑‑
adverse events, and from five phase I/II studies we obtained hematology
and biochemistry parameters.

What has been important for us is to have a consistent study population
in different studies. So the study population that has been targeted in
our program has been low-risk superficial and nodular BCCs. This has
been included in four controlled studies, while we also in two studies
have examined the efficacy and safety of MAL-PDT on high-risk nodular
and superficial BCCs.

The definition that has been used to include patients or characterize
the lesion as high-risk has been lesions in the H-zone or on the
mid-face and ear. The lesion could also be included if they are large
fitting into specific characteristics depending on the lesion site, if
the lesion also had a recurrence or was recurrent after previous
treatment, because it was considered high-risk, and if lesions appeared
on very severely sun-damaged skin.

It is important information that in all the clinical studies, both in
the high-risk as well as in the low-risk, morpheaform or infiltrative
lesions have always been excluded. It is also important to mention that
in the low-risk superficial and nodular BCC studies, these high-risk
lesions were exclusion criteria.

So there have been two programs that have gone in parallel. That is the
efficacy evaluation of MAL-PDT both in low or non-high-risk BCC in four
controlled studies, two vehicle-controlled and two active-controlled
studies, and then two studies in the high-risk population.

The safety of MAL-PDT has been obtained through phase I/II and III
studies and will be presented both from the AK program that consisted of
383 patients and from the clinical studies in BCC containing 538
patients. In addition to that, the safety is also obtained from a
compassionate use study with more than 1,000 patients in Norway, and we
have also conducted three special safety studies in healthy subjects.
Then we also have post-marketing data for more than 35,000 AK and BCC
patients from Europe.

Thank you. Then I will give it over to Dr. Pariser.

DR. PARISER: Thank you, gentlemen. Thank you to the group. As long as my
voice holds out, I would like to spend the next few minutes talking
about the clinical trials that I was involved in as an investigator, in
one of them, the four trials that were just mentioned, and then make
some comments about basal cell carcinoma in general and where this
treatment might fit into the regimen and armamentarium, into the tool
box that Dr. Stern described that\'s available for treatment of skin
cancer now, basal cell now.

Well, in the United States, as well as elsewhere, eradication of the
tumor for treating basal cell carcinoma is usually and almost always the
goal of treatment and is the primary goal that is sought. Cosmesis is
extremely important and maintenance of maximum normal tissue
preservation as well. Only in certain selected cases is palliation or
observation really a goal.

Dr. Stern reviewed very well the standard treatments that we have now
for basal cell carcinoma, both high-risk and low-risk. He rightly talked
about the 90 percent or more of patients that are treated by the primary
methods of electrodesiccation and curettage, cryosurgery, excision, and
Mohs. But I want to try to frame photodynamic therapy as in the
\"other\" category, the category where we think about radiation therapy,
topical 5‑FU, and other treatments for in situations where any surgical
modality may not be the appropriate treatment.

As we decide what to do and how to treat basal cell carcinomas
clinically, we look at various factors: the anatomic location, the
histologic type, whether the tumor is primary or recurrent, how big it
is, and the patient characteristics too, the cosmetic concerns of the
patient. We may treat a 25-year-old with a basal cell a little
differently than a 75-year-old. Patients may have preference for various
treatments. There are comorbid conditions or concomitant illnesses that
affect the choice of therapies frequently, as well as the physician\'s
skill that was mentioned by Dr. Stern and preference. Of course, we have
to think about cost of treatment.

There really is no uniformly established standard of care for basal cell
carcinoma. We all do this every day. All clinicians and dermatologists
treat basal cell carcinomas every day, but there really are essentially
no randomized controls of the modalities of treatment we currently use
all the time. The heterogeneous population of patients and of lesions
makes it difficult to produce algorithmic guidelines which would apply
to treatment of all basal cells. So the lack of uniformity in the
populations and the lack of outcomes make reporting difficult, and there
really are no studies that adequately compare, in the same study side by
side, cure rate, cosmesis, satisfaction, and cost. The study that Dr.
Stern cited is, of course, a meta-analysis and very good data, but
doesn\'t compare all the modalities in the same study.

So the meat of what I want to present to you, the sort of core of this
development program of this drug, has been the two double-blind,
vehicle-controlled studies and two active comparator studies, the active
comparators being excisional surgery in one study and cryotherapy in the
other study. All of these four studies which I\'ll describe for you were
prospective multi-center, randomized studies with parallel group design.

Of primary importance is the study of MAL-PDT in low-risk basal cell
carcinoma, and these are the vehicle-controlled studies known as 307 and
308.

The 307 study was conducted at 8 sites in the United States. Here is the
list. I was an investigator in this trial. The pathology for this was
all done in a central lab in Rochester. Dr. Gibson was the pathologist
who examined all the specimens.

The Australian study, identically designed, was carried out in seven
sites in Australia, and Dr. Murrell is here as an Australian
investigator, and these are the folks who did this particular study.

The inclusion/exclusion criteria for the studies were exactly the same.
Included were only primary nodular basal cell carcinomas not previously
treated. The exclusion criteria for these lesions were large lesions,
and \"large\" was defined differently for different places on the body:
20 millimeters for extremities, 30 millimeters for trunk, and 15
millimeters for face. Also excluded were lesions located in the
mid-face, those ones which are a little more problematic clinically, and
morpheaform lesions were excluded from all the trials.

In order to precisely and accurately identify where the lesions were and
to be able to be sure that the proper lesion was being evaluated in the
follow-up periods and to guide where the excision was going to be at the
end, India ink tattoo marks were used to mark the lesions. I will show
you a little picture about how that was. The four tattoo marks were
excised at the end of the study during the surgical excision.

So here\'s a small tumor and I think you can see the four India ink
tattoo marks at the visual external margins of the lesion which were
used to locate the lesion during the study and were used as a guideline
for excision at the end.

The specimens were all examined histologically in a breadloaf fashion in
the central laboratory with sections cut not in Mohs fashion, but in
breadloaf fashion, as you see indicated. Multiple sections were taken.
In the 307 study, this is the number of sections examined per millimeter
of length of the specimen, so just under one in the 307 and almost
one-and-a-half sections per millimeter. So there was quite a bit of
sectioning done in the breadloafing of that piece of tissue.

The investigators were trained on the technique of performance of the
MAL-PDT by on-site demonstrations and each individual investigator site
both in the U.S. and in Australia. The same two trainers trained all the
investigators. Some of us even had the chance to visit Oslo and learn
how to do it in Norway. There was an instructional video that was
supplied to all the investigators, as well as the written instructions
which were in the protocol. So these are these items supplemented the
written instructions.

Now, there was a question before about the lesion preparation. The idea
of the lesion preparation was not to do a therapeutic curettage by any
shape of the imagination. The idea was to remove the surface epidermis,
a bit of the tumor to allow the medication to penetrate and the light to
penetrate into the depths of the tumor. This is something which was done
without anesthesia, to answer the question, and it was a very surface
debridement not intended to be a therapeutic curettage. We will have a
discussion about whether in fact in some patients it may have been a
therapeutic curettage, but that certainly was not the intent.

The primary efficacy variable of the study was the complete histologic
response in a patient. So for a patient who may have had multiple
lesions to be counted as a responder for the primary efficacy variable,
all the lesions within any individual patient had to be totally and
completely cleared histologically. That was the endpoint of the study.

Secondary endpoints that were looked at were the histologic rate by
lesion as opposed to by patient, the clinical outcome by patient and by
lesion, as well as the cosmetic assessment by the investigator and the
patient.

Also, the safety variables were looked at as well and they\'ll be
assessed in a separate presentation on the safety from all the studies
combined.

Definitions which were used in the study and which I\'ll refer to in the
results here are as follows. A patient histologic response assessment. A
complete response was defined, as I said before, in a patient where all
lesions within that patient had a complete histologic response, and the
meant complete disappearance of all tumor cells. And a non-complete
response was not complete disappearance of tumor cells.

In terms of the clinical efficacy evaluation, a complete response was
defined as complete disappearance clinically of the lesion, no
perceptible lesion clinically. A partial response was defined in a
lesion where the longest diameter of the lesion was decreased by half or
more, 50 percent of more, and a patient was judged as having no response
‑‑ there may have been some change in the diameter of the lesion, but
less than 50 percent. Those patients were deemed to have no response.
And then the term \"progression\" was used if the lesion enlarged by 20
percent or more. So those were the definitions for the trial.

In terms of the cosmetic outcome assessment, the signs assessed were
scarring, pigmentation changes, atrophy, induration, and erythema. Those
were graded according to the definitions that you see on the right side
of the slide.

Now, this is the flow diagram for the studies 307 and 308, the two
placebo-controlled studies. Now, the patients, after randomization in
the study, either had MAL-PDT or vehicle-PDT which was a sham PDT
procedure with the same lesion preparation, the same application of
medication, the same illumination, only the active ingredient obviously
was not in the cream. These patients received one treatment cycle, which
is defined as two treatment sessions 1 week apart. So the MAL-PDT or
vehicle-PDT was applied and performed 2 weeks apart, and then the
patients were followed for 3 months.

At the end of the 3 months, the patients were judged as having a
complete, partial, or no response, and if they had a complete clinical
response, they went into a follow-up period where 3 months later, the
lesion was excised in a breadloaf fashion that I described for you.

If they had a partial response, they were treated with another cycle of
PDT, defined as two more sessions 1 week apart. That was either the
vehicle or the active.

If they had no response, the lesion was excised and they left the study.

Then those patients who had a second treatment were followed for 3
months after that and were either clinical responders, in which case the
lesion was excised, or an incomplete response, in which case the lesions
were treated and the patients left the study.

There were 65 patients with 80 lesions included and treated in this
trial, the 307 trial, that were randomized roughly 50-50 to the MAL-PDT
or the vehicle-PDT. Two protocol deviations happened to have been in the
active drug group for the reasons that you see at the bottom of the
slide, leaving the following numbers in the sample size of the study
patients.

In the 308 study, the numbers are similar and discontinuations were
similar. You can see the reasons for discontinuation there. So the total
numbers of patients are per protocol, as you can see in the bottom
boxes.

Looking at the demographics of the patients in both studies, there
really was no significant difference. The only thing that does show up
on this slide is that in the 308 study there\'s a little discordance in
the gender of the patients. That really was not deemed to have any
clinical relevance.

Most patients had 1 lesion that was treated, the large red bar. A few
patients had 2, 3, or 4 lesions. Remember that for a complete response
in a patient who did have multiple lesions, all of the lesions had to be
histologically cleared. So a few more in the 307 and a few less in the
308 with multiple lesions, but the vast majority of patients did have
only 1.

Now, this is the primary efficacy variable, the meat of the
presentation, if you will. This is the patient response rate to the
study in the 308 and the 307 by patient listed first and then by lesion.
So the primary efficacy variable of the study which was the patient
complete response: in the MAL-PDT, 67 percent in the 308 and 78 percent
in the 307 study, as opposed to 18 and 33 in the vehicle-PDT. This is
the primary efficacy variable which does have a greater than .001 p
value. So that\'s the cure rate of this treatment in this study,
displayed on an intent-to-treat basis.

Lesion response, actually very similar numbers as opposed to patient
response.

There really was not any significant treatment-by-center interaction in
the primary efficacy variable, although there was some variation in the
center-by-center results. In every center there was a higher response
rate for the MAL-PDT compared to the vehicle-PDT, and there were two
sites with very small numbers of patients that did have extreme values
that contributed 20 percent of the data in the primary analysis.

Looking at the cosmetic outcome of the patients in both the 307 and 308
studies, as you can see, the vast majority of patients and investigators
rated the cosmetic improvement as good to excellent. No one rated it
poor.

So the efficacy conclusions from these two blinded vehicle-controlled
studies, the primary efficacy variable was demonstrated and that was a
statistically significant difference in the active versus placebo group
in these two controlled studies based on the primary endpoint of
complete histologic clearing.

Now, I\'d like to switch gears and talk about two additional studies,
and these are active comparator studies which were done outside the U.S.
and in which I personally was not an investigator.

There are 13 sites in the Europe in the 303 study. This is the 303
study, a randomized trial, obviously not blinded, but a randomized trial
of MAL-PDT versus simple excision for primary nodular basal cell
carcinoma conducted by these 13 centers.

The second study we\'ll talk about is MAL-PDT versus cryotherapy in
superficial basal cell carcinoma, again a prospectively randomized study
conducted in these 12 sites in Europe.

Now, the main objective of these two studies looking at them together is
to compare the response rate in a controlled population in a prospective
fashion of these two modalities, cryosurgery and excisional surgery, to
MAL-PDT.

Now, in designing this protocol, the protocol was designed to pick up a
clinically relevant difference of 15 percent or more in the response
rate. So the study was designed to pick up a greater than 15 percent
difference. In order for that to happen, the confidence limit had to be
above the negative 15 percent.

Secondary objectives were the cosmetic outcome, adverse events in all
the studies, and long-term follow-up.

The inclusion criteria for these two studies were similar to the others
in the case of untreated nodular basal cell or superficial basal cell
carcinoma and the patients and lesions had to be suitable for treatment
with the comparator to be randomized in the comparator study. The
high-risk lesions were excluded. The morpheaform lesions were excluded
and the infiltrated lesions were excluded, as defined previously.

So you\'ll see this looks pretty similar, the study diagram. The
patients who were randomized to MAL-PDT had the same cycle of two
treatment sessions, 7 days apart; 3 months later were judged to have a
complete or non-complete response. The non-complete response patients
had another cycle of PDT, two sessions 7 days apart, and then were
followed for 3 months, as were the ones who were complete responders
after the first treatment cycle.

Histology was not done at the end because this study involved long-term
follow-up.

So those patients who were randomized to surgery in that same study had
the surgery, and 3 months later were evaluated as either complete
responders or non. If they were complete responders, they went into the
follow-up, and non-complete responders were dropped from the study.

In the comparator study versus cryotherapy or cryosurgery, these
patients, those who were randomized to the MAL-PDT group, had one
treatment session of MAL-PDT and 3 months later it was decided whether
it was a complete response or non-complete. The non-complete had the
usual two treatments in the treatment cycle, and responders went into
follow-up. It\'s a bit complicated, but the ones who had cryo in this
study were followed at 3 months after the cryo. The complete responders
went into the follow-up, non-complete responders in the study were
retreated with cryo and then were either deemed to be complete
responders and went into follow-up or non-complete. So I hope I\'ve
explained that satisfactorily.

In terms of the excisional group, this simple excision was done with a 5
millimeter margin, a very generous margin for excision of basal cell
carcinoma, probably much more generous than done in clinical practice
when excision is done for basal cell carcinoma.

The cryotherapy, just the details of how that was performed. It was done
with liquid nitrogen. The lesions were frozen to an icefield of a 3
millimeter margin around the lesion. It was allowed to thaw for two to
three times the freeze time, and then a second cycle of cryotherapy was
applied for a minimum of 20 seconds.

In the 303 study, 103 patients randomized; in the 304 study, 120. So
those are the n\'s that we\'re dealing with.

Demographics in the two studies together showed no real difference in
the populations going into these studies.

In the excisional surgery study, most patients had 1 and only a few
patients had 2 lesions. In the comparator study, a superficial basal
cell carcinoma with MAL-PDT, many more patients had more than 1 lesion,
and that\'s of course a common presentation for superficial BCC.

This is looking at the primary efficacy variable 3 months after the
treatment. The patients who had the MAL-PDT, 45 out of 50, or 90
percent, met the criteria of cure; that is, they were cleared. The
comparator, surgery, was 98 percent. The confidence limits for this
particular study, displayed here as MAL minus comparator, do not
encroach into that 15 percent window that we talked about earlier. So
these patients did meet the primary efficacy variable.

Similarly, the MAL-PDT versus cryo was even better, 95 percent. It
actually beat the cryo and certainly was well within that 15 percent. In
fact, it was on the other side. That was patient complete response rate.

Looking at lesion complete response rate, the MAL-PDT versus surgery,
looking at lesion by lesion, 91 for MAL-PDT, 98 for surgery, and in the
cryotherapy, 97 for MAL-PDT and 95 in this population.

Looking at the cosmetic outcome, pretty much all surgery by definition
leaves scars, and so scarring would not qualify as an excellent
improvement most of the time. But you certainly can see that the
investigators and patients rated the MAL treatment excellent or good,
much higher than the surgery, particularly the patients who seemed to
like it more.

Looking at the cosmetic outcome of the cryo versus MAL-PDT, the same
things are found. The cosmetic improvement was rated much higher with
MAL-PDT than it was with cryo. Dr. Stern so rightly talked about those
hypopigmented scars that we get from cryo all the time.

Now, this is an attempt at a life table to follow over time what the
recurrence rates may have been, and I\'ll show you what\'s available to
date about this. At the 2-year follow-up point, 8 out of 53, or 15
percent, of the MAL-PDT patients were treatment failures, and 1 out of
52, or 2 percent, of the surgery patients were treatment failures. This
line and this line are the number of patients who are missing, lost to
follow-up, and not included in the table.

So here is the table going out to 24 months. Now, this is going to be
extended all the way to the 5-year point, which is how the study was
originally designed. But you can look at the time to treatment failure
in the top line for surgery at the data points indicated and the MAL-PDT
at the data points indicated.

Looking at the cryotherapy comparator study showing the same data, there
was a 25 percent treatment failure at 3 years. This is new data, and I
think this is part of the information that the agency has. This is a
little longer on the cryo 3-year follow-up. 25 percent treatment failure
estimate for the MAL-PDT, about the same estimate for the cryo. Those
curves are pretty much superimposable.

So the conclusions from these two comparator studies were that MAL-PDT
did give a similar initial response rate and a sustained response rate
very similar to cryotherapy in this prospective randomized trial versus
cryotherapy for superficial basal cell carcinoma. Regarding the MAL-PDT
response in excisional surgery for nodular basal cell carcinoma, there
was a similar initial response but a lower sustained response rate
compared with surgery, still however meeting the criteria of 15 percent.
Also, the other conclusion was that the MAL-PDT was judged by
investigators and patients to have a superior cosmetic outcome.

I will now introduce Dr. Dedee Murrell to talk about some of the studies
in the higher-risk patients.

DR. MURRELL: Thanks, David.

I\'ll be presenting the results of MAL-PDT in the high-risk basal cell
carcinoma patients. In addition to being an investigator on one of these
studies, because I\'ll be presenting two, I was also an investigator on
the 308 study that you just heard about and also a randomized controlled
study of MAL-PDT for actinic keratoses.

I\'m a dermatologist trained in the United States at Chapel Hill, have
trial experience at Duke, and was on the full-time academic faculty at
NYU and Rockefeller prior to going into clinical academic dermatology in
Sydney. Of course, practicing in Australia, I treat a lot of patients
with skin cancers and refer patients to Mohs surgeons there too. So the
practice is not that dissimilar from practicing here.

In Europe, these were open, uncontrolled studies in a high-risk group of
patients, and the dermatologists and the sites shown in Europe are
eight, shown here. It was not felt appropriate by these investigators or
their ethics committee that it would be ethical to randomize these
patients to an alternative treatment, and hence, they were open,
uncontrolled studies.

And these are the eight sites where the separate study was conducted in
Australia.

This shows the flow-through diagram that you\'ve seen before. In these
two studies, the 205 study consisted of 94 patients with 123 BCC
lesions, and the 310 study, 102 patients with 165 lesions, making 196
patients altogether.

Now, the definition of high-risk BCCs in this trial, as you know, did
not include the morpheaform or multi-focal, micro-nodular BCCs, but it
did include in the 205 study large basal cell carcinomas which was
defined in this instance as being greater than 20 millimeters on the
extremities compared with 15 millimeters on the extremities in the 310
study; greater than 30 millimeters on the trunk in the 205 study and
greater than 20 millimeters on the trunk in the 310 study; and the same
size, greater than 15 millimeters on the face.

Both studies included BCC lesions located in the mid-face defined as the
nose, nasolabial fold, and orbital area, or ear in the 205 study and
similarly in the Australian study, including Swanson\'s described
H-zone, which includes the temple.

In the European study, recurrent BCCs were included, and they were
defined as a treatment failure after two previous treatment within a
year. In the Australian study, we included a group of patients at high
risk for surgical complications, and these were patients who may not
have been able to have surgery because of bleeding problems, patients on
anticoagulant medications such as warfarin, or were unsuitable for
surgery for other medical reasons.

In the 205 study, there was a subgroup of patients who were severely
sun-damaged and it was felt that surgery and radiation therapy was not a
good option for those patients due to their frequent recurrence.

Although these pictures do not depict all our patients, they\'re just to
give you a flavor of the types of patients that were included. In the
205 study these patients have central facial lesions, here on the
forehead, the tip of the nose, a young woman with one above the lip, and
one behind the ear. There was a large group of patients with multiple
superficial basal cell carcinomas such as this man on the trunk and this
woman with the superpubic lesion here. And this is an example of a
couple of the severely sun-damaged patients. I believe this woman had at
least 10 lesions included in the study, and this man, who has had lots
of previous surgery, who had a new BCC on his cheek here.

In the 310 study in Australia, we also had H‑zone lesion patients. This
is one of my patients here, a young woman with a BCC on the temple and
another young woman with one on the nose.

In the 310 Australian study, we also included quite a number of patients
with large BCCs below the knee. As we all know, this presents surgical
problems from the point of view of primary excision and closure because
you don\'t get lots of excess skin on your lower legs, and also
circulation problems. These lesions often have to be treated with grafts
and flap surgery. This is one of my patients who was diabetic and
elderly, an 80-year-old woman with a large BCC on her lower leg with
peripheral vascular problems, and another one of my patients who had
AIDS and hepatitis B who had a large nodular BCC on the dorsal of his
foot.

So having said that, the study protocol was similar to the ones you\'ve
just heard about. The patients had two sessions, one treatment cycle, 7
days apart, as you\'ve heard. Then they had an assessment performed at 3
months in which, if it was clinically felt they had had an incomplete
response, they then went and had another MAL-PDT cycle of two sessions
again. However, if it looked as if they had complete response, then they
had biopsies taken, which I will explain to you in a moment, and as long
as those biopsies were clear, these patients are being followed annually
for 5 years. These patients who underwent two treatment cycles 3 months
after the last treatment cycle had the same assessment, and if it was
complete on biopsies, they went into the 5-year follow-up group. And
those patients where the biopsies showed there was still BCC present
went on to alternative treatments and had to drop out of the study.

This shows the type of assessment that was done at the 3-month period
after the last PDT treatment, and patients, in addition to having body
maps done, of course, and templates to mark out the lesions, if they
were large lesions, had this stamp put over the lesions, and in the 310
study, a 2 millimeter punch biopsies was taken from every square
millimeter of that stamping area. In the 205 study, one biopsy was taken
per lesion from the clinically most suspicious part of the lesion.

In addition, in the 205 study, they had an independent reviewer who
reviewed photographs and histology reports from the lesion at the point
where the patient was recruited. This reviewer excluded 9 patients after
going through this process in this study. In addition, the independent
reviewer reviewed the cosmetic outcome and response on pathology 3
months after the last PDT treatment.

Now, to the results of these studies. This shows the percentage of
lesions by patient, and you see that in both studies the majority of
patients had 1 lesion, especially in the 205 study. In the 310 study, 19
percent had 2 lesions.

This bar graph shows the percentage of patients having different types
of BCC lesions. In the 205 study, there was an equal distribution
between superficial and nodular types of BCCs, and as expected, the
majority of the nodular lesions were on the face and scalp shown in red.
In the 310 study, there was 50 percent of lesions which were
superficial, and the other 50 percent was equally divided between
nodular lesions and mixed nodular/superficial types. Typically most
superficial BCCs were on the trunk.

The size of the lesions was similar between the two studies: 23
millimeters for 205 and almost 20 millimeters for the 310 study.

The distribution of the types of high-risk lesions included was similar
in that the large lesions comprised about 50 percent of both studies:
the mid-face lesions, a higher proportion, 43 percent in the 205 study;
29 percent, H-zone lesions in the 310 study.

In the 205 study, 13 percent of lesions were recurrent, defined as two
recurrences within 1 year. Surgical risk only patients comprised 16
percent of the 310 study patients, and 15 percent of these study
patients were the severely sun-damaged patients.

This is our primary efficacy endpoint result by patient. So every
patient had to have all of their lesions completely responding and by
intention-to-treat analysis at 3 months after the last PDT treatment. In
the 205 study, it was a 72 percent response by patient, and in the 310
study, an 80 percent response.

This shows for the 310 study the results broken down by type of
high-risk category, and you\'ll see that the patients at high risk
because they were unable to undergo surgery had a 100 percent response,
and the other high-risk subgroups had similar response rates in the low
80s.

The lesional complete response rates, which we would expect to be
higher, by intention-to-treat analysis in the 205 study was 75 percent
and in the 310 study 85 percent. The cosmetic outcome was graded in the
205 study by the investigators and the independent reviewer and found to
be good to excellent in most cases, and in the 310 study, by the
investigator and the patient, and again found to be good to excellent,
with higher ratings by the patient.

These are these life tables again, the time to event tables. The pink
line shows you the results for the 205 study going out to 36 months, and
the blue line, the 310 study, going out to 24 months, 2 years. These
numbers just give you an idea of the numbers of lesions that were
present at the beginning of the study and that are being followed
currently. So that gives you a good idea of the treatment failures at
the beginning and then the recurrences that are developing with time.

So, in conclusion, from these two uncontrolled studies, the 205 and 310,
in this definition of high-risk BCC we see some supportive evidence of
efficacy and especially utility in some patients with these types of
high-risk superficial and nodular BCCs. I believe that MAL-PDT offers an
alternative treatment ‑‑ not a primary treatment, an alternative
treatment ‑‑ for BCCs when Mohs might not be the usually used or
preferred treatment. Such examples might include some of these multiple
large superficial BCCs, patients with lower leg lesions, and patients
with medical contraindications for the use of surgery.

In addition, the studies demonstrate good to excellent cosmetic outcome
in patients with central facial and ear lesions and large superficial
BCCs.

Now, we will have the important presentation on the safety results from
all of our studies by Dr. John Posner.

DR. POSNER: Thank you. Good morning, ladies and gentlemen. My name is
John Posner. My background is internal medicine and clinical
pharmacology in the pharmaceutical industry, and I\'ve been working as a
consultant independently with PhotoCure now for the last five years.

I\'m going to present the safety data on the BCC and AK population, the
total experience that we have with this product. I\'ll start with some
definitions and methodology, describe the safety patient population, the
adverse events, a brief word about clinical laboratory data, and finally
the important subject of irritancy and sensitization.

Adverse events and serious adverse events were defined in accordance
with the ICH guidelines on good clinical practice.

To err on the side of caution, treatment related were considered all
those that are classified by the clinicians as yes or uncertain.

The period of recording is important to note. They were different for
actinic keratosis lesions where the period of recording was confined to
3 months after the last treatment, that is to say, when the final
assessment was done; whereas with the basal cell lesions, it went from
the randomization to 6 months for all adverse events and then continuing
during the whole of the recurrence period for serious adverse events
which, of course, includes deaths. Currently we\'re just coming up to 3
years. In some trials we\'re there and some we\'re not quite there.

The coding I\'ll say a word about in a moment when we look at the
non-local adverse events, but essentially local adverse events are those
applying, according to the WHO classification systems of system organ
classes, to skin and appendages. There are some terms that are not in
the dictionary like bleeding skin, tingling skin, and pain in the skin
that were added by the sponsor. The non-local adverse events are all
those adverse events relating to other system organ classes.

The population then. We have clinical trials in basal cell carcinoma,
which you\'ve heard about, of 538 patients. That also includes the early
phase I/II studies with a relatively small number of patients. Clinical
trials in actinic keratosis here as 383 patients, compassionate use of
over 1,000 patients, and some post-marketing experience currently up to
about 35,000 patients.

Most of what I\'m going to be talking about, of course, is the clinical
trial population, and here the clinical trial safety population is the
same as the intent-to-treat, which is all patients randomized to
treatment who received at least one dose of the randomized medication or
who underwent at least one of the other interventions.

All the MAL-PDT patients in BCC are mentioned here, 538 patients with
857 lesions and over 1,600 PDT sessions because, of course, many of them
had two or more sessions. In addition, we have these 383 AK patients,
but because of the number of patients with multiple lesions, we actually
have over 2,000 PDT sessions here, and the total comes to nearly 4,000
sessions of MAL-PDT.

Now, the number of clinical patients in clinical trials with treatment
emergent adverse events. Here you see the 538 BCC patients, and about 80
percent of the patients had adverse events. As you can see from the
breakdown, 75 percent of those, three-quarters of those, were local
adverse events, and 27 percent are classified as non-local. In AK,
actually the profile is very, very similar: 74 percent local and 22
percent non-local.

The deaths and serious adverse events. In the BCC population, we have 18
deaths and we have, in terms of serious adverse events, about a 5
percent rate here. None of the deaths and none of the serious adverse
events, with the exception of one, were considered to be
treatment-related and they certainly weren\'t local.

This one local serious adverse event was a patient who had severe pain
at the time of illumination and the patient required admitting to
hospital, and for that reason was considered a serious adverse event.
The patient received analgesia. The pain subsided and he went home the
next day.

You\'ll notice that the death rate here, the mortality on the BCC, is
considerably higher than that with AK. This simply reflects the duration
of follow-up. Here we\'re talking about elderly patients being followed
for 3 years and inevitably there will be deaths. We\'ve obviously looked
very carefully at all of these and there isn\'t anything that is even
vaguely treatment-related there. AK was a much shorter period of
follow-up.

The non-local adverse events. So these are not the serious ones, but
they are classified as non-local. I want to make the point that there is
very little evidence of systemic adverse events. In fact, the commonest
cause for a non-local adverse event was a basal cell carcinoma
discovered at another site. This was coded, according to the system, as
a neoplasm and, therefore, because it didn\'t fall under skin and
appendages, got classified as a non-local adverse event. Clearly it\'s
not systemic.

The same applied to surgical intervention for a preexisting skin lesion.
So the surgical intervention in that case went down as a non-local
adverse event.

If one then removes those, because they\'re not systemic, one is left
with a variety of individual symptoms as you would expect,
influenza-like symptoms, occasional reports of headache, and then even
more occasional dizziness or blurred vision. I should point out any
reports of blurred vision we\'ve looked into carefully. They were not
local to the site of treatment.

So our conclusion from careful scrutiny of these non-local adverse
events is that in fact there\'s no evidence of systemic effects of this
treatment.

Now to the local adverse events, and the vast majority of these were
treatment-related. They come under really this complex of symptoms and
signs which we call phototoxicity. Typically it is pain or discomfort at
the site of illumination on treatment. The pain is often described as
burning or stinging, and also the other most common adverse event of
this nature that goes into the phototoxic complex is erythema, almost
invariable. Edema of the skin is also frequent.

If we look at the profile of the relative incidence of these for the
total population of BCC and AK, we\'re talking about erythema being the
most frequent. Pain in the skin, burning skin, we also have stinging
skin there, the edema, local pruritus, crusting, blisters, suppuration.
And this goes down to the 5 percent level. You have a more complete
table in your briefing document that goes down to the 1 percent level.

I should point out that the numbers are quite inflated here because if a
single patient said that they had pain and they also said that they had
burning and stinging, that went down as three separate adverse events
which were all rated.

The severity. The majority of them are mild or moderate, but we do have
some patients, averaging about 10 percent, which are classified as
severe. This was usually pain. So 1 in 10 patients approximately will
have complaint of severe pain beginning at the time of illumination and
subsiding rapidly afterwards. There was no difference in any of these
between the basal cell carcinoma and the actinic keratosis populations.

Despite this high incidence of phototoxic adverse events, the
discontinuations really were few and far between. In the basal cell
population, we just have .7 percent actually discontinuing, and AK, just
slightly more than that, an average of 1 percent withdrawals.

The duration of the local adverse events. Skin pain, burning, stinging,
tingling, as I say, generally starts at the time of illumination and
then subsides over the next few hours, and the median time is less than
1 day, so generally on the day of treatment, subsiding rapidly.

Edema and other inflammatory signs you see listed here typically lasts
for a few days up to 1 week, and erythema and crusting, as you would
expect, skin ulceration occasionally, suppuration infection in about 1
percent of patients generally resolve within a couple of weeks.

We were interested to know if the number of local adverse events,
phototoxicity, increased or decreased with the number of sessions that
the patient receives. So we\'ve broken this down by the number of
sessions and the incidence of local adverse events in this BCC
population.

So here we see 250 patients who received two sessions. In fact, we find
that the incidence of phototoxic adverse events decreases. Here we have
94 patients who had four sessions and we see that it\'s actually
declined pretty well from at least the third session of PDT. So we can
say that there\'s certainly no increase in the number or the severity of
adverse events with repeated application.

Looking at the comparative data ‑‑ and, of course, although these
studies were powered adequately for efficacy endpoints, they are small
in terms of safety. But if we look at the difference between the MAL-PDT
and the placebo or vehicle-PDT groups, in this particular population, we
do see a difference, the typical 74 percent here for the MAL-PDT, but
almost half the patients receiving the placebo or vehicle treatment also
had local adverse events, no doubt reflecting the preparation, cream
application, illumination procedures.

In terms of non-local adverse events, the percentages here are slightly
higher in the MAL-PDT but very few of these, four cases, were considered
to be related here and two there. So the vast majority of these are not
considered to be treatment-related.

The severity: mild, 47 percent; moderate, 53 percent; no severe here in
the MAL-PDT. The placebo really rather similar.

The results in comparison with surgery are confounded by the fact that
all the patients who had surgery had local anesthesia, whereas those
with MAL-PDT did not. So it\'s really rather difficult to interpret
these results, but what we can say is that under the local anesthetic,
the surgery incidence of local adverse events is 16 percent versus the
MAL-PDT of 50 percent not under local anesthetic. No difference in the
number of non-local adverse events. Here the severity, all of the
surgical ones were mild.

Cryotherapy. The results in terms of adverse events and particularly
local adverse events are very similar with MAL-PDT and the cryotherapy,
70 percent, 78 percent; and non-local here, 28 percent, 36 percent, the
vast majority again not being considered to be treatment-related. The
severity of these is rather similar for the two treatment modalities.

Those are the clinical trial data. We then have the compassionate use
study in which just over 1,000 patients were treated in Norway, mostly
at the Norwegian Radium Hospital, but also in some other centers. These
were patients with a variety of lesions, mostly BCC, and nearly 1,500 AK
lesions and some other non-melanoma skin cancers. There was no formal
GCP here, good clinical practice, as performed in clinical trials, but
there was some collection of solicited data on pain and erythema, and
the outcome essentially is in line with the clinical trials, that the
majority of patients have pain and erythema, but there were very few
non-local adverse events.

We do have some post-marketing experience. The product was launched
initially in October 2001 in Sweden, and in the last year and
particularly in the last few months, we have the UK and Germany coming
on stream, plus three other Nordic countries. So by June of this year,
we have some experience of an estimated 35,000 patients which probably
represents certainly over 50,000, maybe as many as 70,000, PDT sessions.

These are the spontaneous adverse reports that have come into the
company either through the regulatory authorities or directly. Most of
them are fairly unremarkable, but I would like to mention these two
classified as eczema by the clinicians.

One of these was considered to be an allergic response, but no patch
test was done, and the description of the symptoms and signs are, in
fact, completely compatible with phototoxicity. It\'s really very
difficult to distinguish that. So we don\'t know whether that was a case
of sensitization.

The other case has been more thoroughly explored. It was a patient with
diabetic necrobiosis lipoidica on the lower legs and had several
treatments with MAL for this condition. The patient developed an
allergic response after several treatments with some blisters, and the
patient was rechallenged with MAL and with ALA some weeks later. The
patient was positive to a skin patch test to MAL but not to ALA.
Actually at the very highest concentration of ALA, 10 percent, there was
a very weak response. Essentially it was a positive skin patch test. And
that is the only definite case, confirmed case, of sensitization that we
can refer to.

We\'ll come back to the question of sensitization in a moment, but just
a word about clinical laboratory data. As has been said, we are
confident that the absorption of this drug is minimal, and so we do not
expect to see adverse events of a systemic nature. But nevertheless,
we\'ve monitored clinical laboratory data in the phase I and II studies,
a total of some 375 patients, and in particular concentrated on liver
function tests because the target organ toxicity at concentrations many
thousand times more than at which a patient would be exposed
systemically was the liver.

To cut a long story short, what we can say is that there was a
completely uniform distribution, quite random, of changes in liver
function in terms of transaminases and bilirubin, with no patient
actually having more than a twofold increase over their baseline value
after treatment, and the vast majority of patients actually having a
change of less than 40 percent. Normally one clinically thinks of times
2 or times 3 the upper limit of normal, and none of the patients showed
this sort of increase. There were, of course, a few patients just
through random distribution above the upper limit of normal when they
started and a few when they finished, but there was really no indication
of any change here. And we conclude that there are no clinically
relevant findings in liver function tests or other laboratory
parameters, and for that reason, clinically laboratory tests were not
monitored in the phase III studies.

Now, the question of irritancy and sensitization and cross-sensitization
to 5-ALA. Two preliminary studies were done in healthy volunteers which
suggested that there was no irritancy for a 24-hour exposure, but if you
exposed for 2 weeks continuously, then you started to get an incidence
of irritation, and when patch tests were done, there was an incidence of
positives.

So a much larger study was set up, this study 110, in which it was
intended to recruit over 200 subjects. These are all healthy volunteers,
and 224 were screened, but in fact because they were in staggered
groups, not all of them entered. The last group was not actually entered
into the induction period, and the reason for that was that it was quite
clear that there was a high incidence of irritancy and it was felt that
it would be inappropriate to just recruit and put in another cohort.

156 subjects had a 3-week application of MAL and its vehicle on the
upper back. MAL and the vehicle cream were applied 3 times a week, so a
total of 9 times during the induction period under Finn chambers and
tape occlusion continuously. They did not have any illumination, and
there was no rest period. At the end of the 3-week induction, they then
had a 2-week rest period, followed by a challenge on the arm with MAL or
its vehicle or 5-ALA and its vehicle.

Because of the high incidence of irritancy, in fact a number of
volunteers by mutual agreement with the investigator, who was Professor
Ronald Marks in the UK who is a specialist in this area, it was agreed
not to challenge them all with the MAL. So actually 58 subjects had the
MAL and the ALA challenge and 40 just had the ALA or vehicle. Then the
challenges were read over a course of 48 hours.

All but 1 subject reacted with erythema during the 3-week induction
period to MAL. The earliest reaction of moderate severity, a grade 2,
occurred after 4 days of constant exposure, nothing before that. There
was very little reaction observed on sites exposed to vehicle.

Sensitization on patch testing of the 58 subjects that were challenged
with MAL, 52 percent had clearly positive reactions with MAL and just 1
subject with the vehicle, and of the total 98 subjects who were
challenged with ALA, there were no positive responses. This is very
important because, of course, ALA is an endogenous material.

The conclusion then is that there is no doubt that MAL can cause
irritation and contact sensitization, but there\'s no evidence of
cross-sensitization to 5-ALA.

We do question the relevance of these findings. Sensitization in
clinical practice has been rare, with just the one confirmed case that
I\'ve described and no other confirmed cases in the clinical trial
population. This one confirmed was from the post-marketing experience.
The conditions in clinical practice are really very different. We have a
short exposure, 3 hours versus 3 weeks continuous, and we don\'t see any
irritancy due to the cream before illumination. Of course, irritancy is
strongly associated with sensitization.

The illumination that is carried out in the normal clinical procedure
after 3 hours results in photobleaching and, of course, phototoxicity.
The photobleaching means that the photoactive porphyrins have all been
destroyed, which is an important feature of the safety, we feel, of this
treatment, and the phototoxic reaction probably has an influence on the
possibility of any immunological response, though that is of course
speculative.

Finally, the occlusive dressing was different, Tegaderm versus an
aluminum Finn chamber and opaque adhesive tape. We can\'t say how
important that is.

So to summarize our overall safety conclusions, we\'ve got experience in
clinical trials of over 900 patients, compassionate use in over 1,000
patients, and post-marketing data from certainly more than 35,000
patients. We have no clear evidence of systemic effects of MAL-PDT. It
does not cause generalized photosensitivity, and it\'s very well
tolerated despite the frequent local phototoxic reactions with just the
1 percent incidence of discontinuation in our trials.

MAL can cause local irritation and contact sensitization, but this was
in a very intensified and prolonged exposure. Importantly though,
despite that, there was no cross-sensitivity to ALA. And definite cases
of sensitization in clinical practice appear to be rare. There\'s only
one confirmed case in the post-marketing.

Thank you, and I\'ll now hand you back to Dr. Hestdal to sum up the
perception of benefit-risk.

DR. HESTDAL: So I will then try to conclude and close the session, and
I\'ve been asked to discuss this benefit-to-risk ratio of MAL-PDT in
treatment of BCC based on the data that we have presented this morning.

This slide summarizes the demonstrated benefits of MAL-PDT. Safety and
efficacy have been established in two vehicle-controlled studies based
on histological endpoints. We have shown that initial and sustained
response rates were similar to cryotherapy through 3 years of follow-up,
and a favorable safety profile has been established in clinical trials
as well as through post-marketing experience. Cosmetic outcome, judged
both by the investigators as well as the patients, is superior to that
of cryotherapy and excisional surgery.

The risks of MAL-PDT that we have discussed is manifold. Firstly,
MAL-PDT was shown to give a smaller initial response and lower sustained
response rate compared to surgery after treatment of nodular BCC.
However, our histology data shows that there is a retained ability to
treat with other modalities in the case of treatment failures.

Secondly, treatment success of MAL-PDT may require a second course of
treatment at 3 months in some individuals. However, our data also show a
similar rate of retreatment with cryotherapy. In addition, BCC treatment
guidelines already incorporate follow-up after other treatment
modalities.

There is an indication of mild to moderate local phototoxic reactions.
However, very few patients withdrew due to these phototoxic reactions.

Lastly, skin sensitization potential has been shown on the basis of
special studies with very prolonged and extreme conditions. However, low
rates are expected in clinical use based on the clinical trial and
post-marketing data.

Therefore, in conclusion, MAL-PDT is a new and unique non-surgical
treatment option for BCC with a favorable benefit-to-risk. We strongly
think that this should be indicated for treatment of nodular and
superficial BCC where surgery is not desirable.

In that way, I will thank you and this is the end of the presentation on
behalf of PhotoCure. I will thank you very much.

DR. STERN: Thank you very much for your presentations.

Because the presentations went over, I would prefer if we only ask
questions of clarification before the break and then went on to the FDA.
There will be plenty of time for longer questions. So let me give three
examples of questions for clarification that I have.

It\'s my understanding that the application is for the treatment of
superficial and nodular basal cell and not for high-risk lesions that\'s
before the agency. These are questions that I hope would be yes/no or
it\'s this or that. Is that correct?

DR. HESTDAL: Could you please repeat?

DR. STERN: Does your application include the treatment of high-risk
lesions? Yes or no.

DR. MORRIS: Yes.

DR. STERN: The application before the agency includes as an indication
the treatment of high-risk basal cells?

DR. MORRIS: No.

DR. STERN: No. Okay, thank you.

DR. MORRIS: It includes data on that.

DR. STERN: Yes, but it does not include it in the application.

DR. MORRIS: No.

DR. STERN: These are all just simply that.

A procedural one, something about the procedure. Before the application
of PDT at each of the sessions, was curette done again before applying
the agent or was it only applied with the first time a patient was
treated?

DR. MORRIS: Maybe we should let the clinician answer that.

DR. PARISER: The one-word answer is yes. Each session of PDT, curettage
and lesion debulking is part of the treatment.

DR. STERN: My third ‑‑ just because the data weren\'t presented ‑‑ and
maybe you should stay there ‑‑ is it looks to me, from the data
presented, that somewhere between one-third and one-half of patients in
the studies had at least three PDT treatments. Is that correct?

DR. MORRIS: Yes, about one-third needed a retreatment. Yes.

DR. STERN: Thank you.

Any other questions of clarification of that sort of yes/no, what did
you do, as opposed to the data and what it means? Yes.

DR. KATZ: Of the lesions in the H-zone, what was the size of those
lesions? That was not enumerated. You told us on the superficial ones.
Do you have that?

DR. MURRELL: They could be small lesions, but I believe some of those
lesions were large lesions.

DR. KATZ: There were no limits on size.

DR. MURRELL: That\'s what I recall.

DR. KATZ: The other question is what was done for the bleeding after the
curettage. Some styptic or you had a little bleeding there?

DR. MURRELL: There was a little bit of bleeding but we never needed to
use cautery for that.

DR. KATZ: Just pressure?

DR. MURRELL: Yes, pressure and when you put the cream on, sometimes
there was a bit of blood mixed in with the cream under the dressing.

DR. KATZ: But no cautery was done, no styptic.

DR. MURRELL: No.

DR. KATZ: Thank you.

DR. DRAKE: Two quick questions. On the cryosurgery, did you use a
temperature probe or was it just all visual inspection?

DR. PARISER: It was visual inspection.

DR. DRAKE: Second question. I should know this but how deep does the
light penetrate?

DR. HANSSON: We actually have a slide of that on the various blue light,
green light, red light. Red light penetrates at this wavelength where
you don\'t have any quenching by heme far into the dermis. So the light
penetration has no limitation for the treatment effect.

DR. DRAKE: I actually would respectfully ask you to ‑‑ we can do it
after the break, but I\'d like you maybe to consult because I don\'t
think you can say there\'s no limitation to how deep light goes. There
are clearly measures of each wavelength about how deep they\'ll go. So
if you could clarify that a little more for me after the break, I would
appreciate that. Thank you.

DR. RINGEL: I understand that for studies 307 and 308 excisions were
done after the tattooing and after the treatments had occurred. What
were the margins taken around the tattoos, or were only the tattooed
areas excised?

DR. PARISER: Well, the tattoos were placed just beyond the visual
margins of the lesions, and the excisions were taken to include the
tattoos. It was not prescribed. 3 millimeters from the lesion and the
tattoo was placed on the edge of the lesion and the excision was 3
millimeters from the lesion. Where the tattoo was in relation to that
was not prescribed by the protocol.

DR. RINGEL: The lesion has completely disappeared because this is a
complete response. So all you see is the tattoo. Was there a margin
taken around the tattoo, and if so, how much?

DR. PARISER: Well, 3 millimeters. It was assumed that the tattoo was
placed at the edge of the lesion. So when the patient came back and was
responding, the 3 millimeters from that included the tattoo.

DR. STERN: Dr. Plott?

DR. PLOTT: My question is similar. Was there any attempt to characterize
the recurrent to incomplete responses after they were excised?

DR. PARISER: In what way? The histologic type of the lesion or ‑‑

DR. PLOTT: To look at was it more aggressive or any characterization ‑‑

DR. PARISER: We can ask Dr. Gibson, the pathologist, to comment about
that.

DR. PLOTT: Well, just yes or no.

DR. PARISER: There was no change in the lesion. We didn\'t convert any
nodulars to morpheaform basal cells.

DR. TAN: So in the vehicle arm, did you use a placebo cream? What kind
of light was used?

DR. PARISER: Well, the vehicle treatment was the exact same cream in the
placebo without the active ingredient and the illumination was the exact
same illumination. So the placebo treatment, as we defined it, consists
of the application of the vehicle cream without the active ingredient,
the application of the occlusion for 3 hours, and the same illumination
as was carried out with the active.

DR. TAN: Illumination is the same.

DR. PARISER: Yes, correct.

DR. STERN: But clearly you\'re not calling these blinded studies.

DR. MORRIS: Yes.

DR. STERN: I don\'t know how you can call it a blinded study when at
least 75 percent of the people get stinging and burning, if not 100
percent, with the agent.

DR. PARISER: Well, the investigator and evaluator of the lesions was not
present at the time of the treatment and ‑‑

DR. STERN: It\'s not patient-blinded at least.

DR. PARISER: Correct.

DR. STERN: Okay.

DR. PARISER: However, some patients on placebo did get a similar
response.

DR. KING: To begin to frame the question that Dr. Wilkin asked about
writing kinds of input for the PDR, generally when you think about
surgery and cryosurgery, et cetera, you think about exclusionary kinds
of things. If you have somebody who has a tendency with cryoglobulin for
cryosurgery, that would be a complication or bleeding in blade surgery.

What did you do to exclude patients who may have undue phototoxic
responses or indeed may have porphyria? I didn\'t see anything about
what are contraindications in the whole description here. So you\'re
saying basically there are no contraindications.

DR. PARISER: That was an exclusion criteria with porphyrias. Some
natural porphyrins are present in the skin which may account for some of
the placebo response in this.

DR. STERN: Any more clarification questions?

(No response.)

DR. STERN: Then we\'ll have a 16-minute recess and be back at 10:20.
Thank you.

(Recess.)

DR. STERN: I\'d like to reconvene the meeting with the beginning of the
FDA presentation on the application for MAL-PDT for superficial and
nodular basal cell cancer.

DR. VAUGHAN: Good morning, Mr. Chairman. Good morning, members of the
advisory committee, invited guests, and attendees.

NDA 21-576 is being reviewed for the use of methyl aminolevulinate
cream, or MAL, sometimes referred to as methyl ALA, with curettage and
photodynamic therapy ‑‑ I\'ll be referring to that as PDT ‑‑ for the
treatment of basal cell carcinoma.

The FDA clinical and statistical review team consists of the medical
review team: Dr. Markham C. Luke, dermatology team leader; myself; Dr.
Brenda Vaughan, medical officer. The statistical review team consists of
Dr. Shiowjen Lee, who is on leave, and Dr. Mohamed Alosh, the
statistical team leader, who will be presenting today.

Curette-MAL-PDT is a drug/device combination, the physical and the
chemical. It is a drug/device combination, and it consists, as you have
seen, of lesion preparation, of curettage, application of MAL cream
under occlusion for 3 hours, cream removal, and illumination with the
CureLight lamp. Although the device is reviewed by the Center for
Devices and Radiological Health, the device is an integral part of the
application for this drug for treatment of basal cell carcinoma.

Now, you\'ve heard some discussion this morning about results in primary
superficial BCC. The agency agreed that one independent multi-center,
randomized, active-controlled study conducted in patients with primary
basal cell carcinoma might be acceptable depending upon evidence of
safety and efficacy being established for the nodular BCC indication.
Therefore, the comments that I will be presenting today will focus on
the primary nodular basal cell carcinoma indication.

It has been established that curette-MAL-PDT is statistically superior
to curette-vehicle-PDT in the treatment of primary nodular basal cell
carcinoma. The issues that we would like for the committee to consider
and discuss today are the adequacy of these studies. You will be asked
to consider the adequacy of the studies for estimating the cure rates
with use of MAL cream based on early histology of the physical studies
and the small number of patients that were enrolled in these studies,
also the minimal recurrence data available for nodular BCC.

You will also be asked to discuss and consider the adequacy of
instructions of lesion preparation, and Dr. Alosh will discuss the
apparently high vehicle-PDT response rate and the wide center-to-center
variability.

Since this is a skin cancer, we\'re going to ask you to consider the
estimate of cure rate for MAL-PDT versus surgery, which we consider the
gold standard.

From the data that have been submitted, there does not appear to be a
systemic safety signal based on the laboratory and reports of non-local
adverse events. However, we will ask you to consider the local safety
surrounding pain and the minimal information provided regarding
anesthesia and pain control and an unusually high contact sensitization
to MAL cream.

Measurements of efficacy. The agency proposed that efficacy be based on
clinical observation and excision histology and that 5-year recurrence
rate data be presented. We agreed that 2-year data would be acceptable
for filing of the NDA. PhotoCure submitted the pivotal studies based on
excision histology alone, other studies based on clinical observation
alone, and recurrence rates based on clinical observation.

Studies that were interpreted for efficacy by the agency for the primary
nodular indication were two vehicle-controlled randomized studies, 307
and 308; one open-label randomized MAL-PDT versus surgery for recurrence
rates. But we also looked at a phase II open-label, non-randomized
MAL-PDT study for recurrence rates which also had superficial patients
enrolled, and I\'ll speak about the problems we have with including this
study for the recurrence rates.

The pivotal studies were two studies conducted, one in the U.S., one in
Australia. Study 307 in the U.S. enrolled only 33 patients randomized to
the curette-MAL-PDT study arm and 32 patients randomized to the
curette-PDT group. The study in Australia also had only 33 patients
randomized to curette-MAL-PDT and 33 patients randomized to the vehicle
group.

I\'d like to draw your attention to the study design and thank the
sponsor also for mapping out the design because it is complex. The study
design consists that patients would receive either one or two treatment
cycles. The first treatment cycle consisted of two curette-MAL or
vehicle-PDT treatment. Treatments were to be identical, conducted 7 days
apart, and followed by clinical assessment at 3 months. If there was a
partial response to the first treatment, then a second treatment,
identical cycle, would be repeated with two additional PDT sessions
conducted 7 days apart.

The pivotal study designs were as follows. At the 3-month clinical
evaluation, this was the time to determine further management. If the
lesion were in complete response, in other words, complete disappearance
of the lesion, the lesion was followed and excised for histology at 6
months. If there were a partial response where the lesion was decreased
by equal to or greater than 50 percent, then a second PDT cycle was
administered. The lesion was followed and excised at 9 months for
histology. If there was no response, that is, if the lesion were
decreased by less than 50 percent, or if there was progression, the
lesion was excised at the 3 months. I want to point out that complete
response is not equal to cure for a basal cell in this study design.

So to review again, there\'s randomization to MAL or vehicle-PDT.
There\'s the first treatment cycle and there were two PDT,
curette-MAL-PDT, or vehicle treatment sessions conducted 7 days apart.

At the 3-month clinical evaluation, if there were a complete clinical
response, the lesion was followed for an additional 3 months and excised
at that time point.

If there was no clinical response ‑‑ but this group also included those
patients with the partial response that was less than 50 percent ‑‑ the
lesion was excised.

Those in partial response whose lesion had been decreased in size by at
least 50 percent received a second treatment cycle, conducted 7 days
apart.

At the 3-month clinical evaluation, following the second treatment
cycle, those lesions in complete response were then followed again for 3
months and then excised.

If those lesions at this evaluation point with an incomplete clinical
response, these lesions were excised. So, therefore, at the end of the
pivotal studies 307 and 308, all lesions had been excised.

Dr. Mohamed Alosh will discuss the statistical analysis of the pivotal
studies.

DR. ALOSH: Good morning. Thank you, Dr. Vaughan.

To discuss the efficacy results briefly, I\'ll be touching an analysis
unit as well as the criteria for assessing the efficacy.

First, as some of the patients could have more than 1 lesion, as you are
aware, we could speak about the lesion response rate or the patient
complete response rate. For the purpose of the submission, the patient
complete response rate was the primary analysis endpoint. The secondary
endpoint was the lesion complete response rate.

The sponsor presented the results for histology alone, and the criteria
for assessing the response was based on the agency recommendation that
it\'s supposed to be clinical and histology. This was based on a
recommendation in a meeting on March 7, 2000 with the sponsor.

In the protocol, PhotoCure reported the results for histology alone. The
reason I bring this is because clinical and histology response rate
would be a subset from histology. Consequently, the response rate for
clinical and histology, you\'d expect it to be lower as we\'ll see. I
would like to repeat Dr. Vaughan\'s comment that complete response is
not equal to cure.

We agree with the sponsor that curette-MAL-PDT is superior to
curette-vehicle-PDT. We are concerned a little bit about the variability
in the success rate estimate for MAL-PDT which might be attributed to
relatively small studies, and this would lead to a wide confidence
interval around the point estimate, as we\'ll discuss shortly.

Then also there is uncertainty about lesion preparation description. The
clue for this, as you can see on the next slide, is we see high vehicle
response rates in this basal cell carcinoma, as well as there is
center-to-center variability. Again, I\'ll repeat that these are small
studies and the statistical findings should be interpreted with caution
because some of the centers have less than 5 subjects per treatment arm.

So to talk about the apparent high vehicle response rate based on the
sponsor-preferred analysis, based on histological evaluation, you can
see here for study 307, you have in the curette-vehicle-PDT 39 lesions.
Out of those, you have 13 lesions that ended up in complete success
using histology alone. So you end up with a vehicle response rate of 33
percent. This is for the ITT population. If you consider the
per-protocol population, you have a 35 percent response rate for the
vehicle.

If you take the patient response, you can see similar results also for
the vehicle. You can see out of the 32 patients, we have 11 of them
successes. So the success rate for the vehicle is 34 percent. If you
look to the per-protocol, they have similar results.

So about a one-third, roughly, response rate. Whether you look to the
lesion response rate or the patient response rate, you have one-third
roughly, the response rate for the vehicle.

If you look to study 308, the result is a little bit lower for the
vehicle, but again it\'s also lower for the active, with a difference of
about 10 percent. I will touch on this briefly on the center-to-center
variability. If you look again to the patient response rate, you could
see about roughly 18-19 percent in this study. So you can see there is
variability across the two studies, and the response rate, whether you
consider the lesion response rate or the patient response rate, in
particular for the vehicle which is very high. There\'s a question of
whether histology is sensitive enough to assess the efficacy or there is
the curettage doing something for the efficacy results.

In the next slide I\'m going to briefly summarize the efficacy results
if one considers the response rate for the clinical as well as
histological evaluation. Here my focus is really on the point estimate
of the response rate, i.e., the success rate. I\'m not interested in the
treatment effect because, as I said, we agree with the sponsor that
it\'s effective.

So you can see for study 307, if you take the patient complete response
rate, it\'s 73 percent, and the 95 confidence interval, this range. So
the success rate could be as low as 54 percent for the active in study
307.

If you look to the success rate for the vehicle, it could be as high as
43 percent. We agree that they don\'t overlap because the p value is
significant, but we can see how much the range is.

Those point estimates, along with the confidence interval, should be
kept in mind in terms of looking to the efficacy of other modalities
such as surgery and the cryotherapy, which the sponsor presented the
results from two European studies this morning.

Similarly, if we look to the lesion response rate, you can see for study
307 the lower 95 percent confidence interval could be as low as 52
percent. For the vehicle, the upper limit for the 95 percent confidence
interval could be as high as 42 percent.

If you look to study 308, again the lower limit for the active could be
as low as 45 percent; for the vehicle, it could be as high as 32
percent. Similarly for the lesion response rate.

I\'m going to touch later on the center-to-center variability. The issue
there is the sponsor presented the results for the first treatment cycle
which show a high success rate, about 82 percent, even though we have
seen the overall efficacy of about 76 percent. I would like to clarify
some disagreement between the sponsor and the agency results here.

PhotoCure, in calculating the response rate for the first treatment
cycle, excluded those subjects who went through the second treatment who
were partial responders. Anyway, this is not the definition of the rate
which is the number of successes over the number exposed or treated in
this example. So the number here in the denominator, 28, is only those
people who were either a success or a failure, because those who went
through the second treatment cycle are excluded.

Now, if we do the usual arithmetic, taking the number of successes over
the total number treated, we\'ll have a success rate of 56 percent.
Similarly, for the vehicle, we expect a drop. The drop is still from 30
percent to 23, but here you can see a big difference in this. And this
is for the histological evaluation.

If you consider a clinical and histological evaluation, the first
treatment cycle is supposed to be if you take the successes over the
number treated, it would be 46 percent for the active and 18 percent for
the vehicle. For study 308, the results are similar.

I think the point here, in terms of calculating those rates, one would
prefer the usual analysis, to have the number of successes over the
total number treated. Basically I think this study design one could
argue that it\'s impossible. It\'s difficult to estimate the success
rate for the first treatment cycle or the second treatment cycle.

The reason you cannot estimate the success rate for the first or second
treatment cycle is because the study design is really complex. The
second treatment cycle is based on a clinical decision regarding the
first treatment cycle outcome of partial response. Basically those who
are partial responders for the first treatment cycle, if they stay in
the trial without a second treatment, we do not know the number who will
end up in success or failure. So we cannot separate for those partial
responders what the contribution of the first or second treatment cycle
is because they are given two treatment cycles and since no
randomization before the second treatment cycle was carried out, it
would be impossible, I think, to separate the effect of the first
treatment cycle from the second treatment cycle. So this response rate
by treatment cycle I think is difficult to put an emphasis on them in
this study.

Having said that about estimating the response rate for the first
treatment cycle, I still believe the data from the first treatment cycle
could be very useful in looking to the center-by-treatment interaction.
The reason for that first treatment cycle will contribute, will have the
largest data set in which every subject has one treatment, and the
majority of the patients are treated once.

On the next slide I\'ll be discussing the efficacy results per center.
Here we have seven centers in study 307. The first, second, and third
columns give you the curette-MAL-PDT, the number of subjects in the
denominator, as well as the numerator, which has the successes. And the
third column is the same for the vehicle. You can see in this study
center 30707 has 5 subjects in the active. All of them ended up in
success. In comparison, we have 5 subjects in the vehicle. None of them
ended up in success.

The point here, I think we agree the first treatment cycle is not the
primary endpoint analysis. But, however, we are trying to explain the
high response rate for the vehicle, and this in a clinical discussion,
we have to look to this data and the first treatment cycle is
appropriate here.

We have the Breslow-Day test for the first treatment cycle of .025,
which is highly significant. If you consider the p value for testing
interaction, it\'s .10.

Then we ran also the Zelen\'s exact test because you have a small number
of subjects in every center, and you have .07. Again, it\'s significant
at .1.

Now, here I have first and second treatment cycles combined in which you
take the clinical and histological evaluation. You can see the
Breslow-Day test is .13, and this is different than what the sponsor
presented, I believe about 26 or 30 because they used histological
evaluation only while the agency recommendation was to have a clinical
as well as a histological evaluation. In the last set of columns, we
have it for the histological evaluation, which should be close to the
sponsor, about 31 percent.

So to summarize, we have some concern about center-to-center variability
for the first treatment cycle.

If we look to the second slide, here we have a similar analysis for
study 308, which is the second pivotal study. We do not see in this
study the center-to-center variability which we see in study 307. I
would like to mention that those two extreme centers in 307, there is
the efficacy result of the 307 by about 10 percent, and we remember
there is difference in efficacy probably between the two studies, the
307 and the 308, of about 10 percent. So whether it\'s related with
something else.

Here we run the Breslow-Day test. You can see there is no significant
center-by-treatment interaction in study 308.

So in summary, we agree with the sponsor that curette-MAL-PDT is
statistically superior to curette-vehicle-PDT for the treatment method
used in the protocol.

For each study, there is a relatively high curette-vehicle response
rate. There is also center-to-center variability in study 307. This
might be attributed to small study size with small centers. It might be
attributed also to lesion preparation for treatment and to the accuracy
of clinical and histological evaluations.

The center-to-center variability in the efficacy results reduces the
reliability in the overall point estimates of curette-MAL-PDT.

Thank you. Dr. Vaughan will discuss further the curettage.

DR. VAUGHAN: Thank you, Dr. Alosh.

To review again, based on the protocol-guided outcome assessment,
curette-MAL-PDT is statistically superior to curette-vehicle-PDT.
However, the high response rates with the curette-vehicle-PDT, as
indicated, was seen, and as touched upon by Dr. Alosh. The high rate in
the curette-vehicle group may have been due to the effect of the extent
and depth of curettage. It may have been due to the short-term follow-up
of 3, 6, or 9 months, or it may have been due to a low ability to detect
residual BCC by histological methods.

This is an example of a curette and lesion preparation provided by
PhotoCure from the PhotoCure video.

Other factors in the pivotal studies appear to be consistent, such as
lamp exposure, MAL cream application time, for each of the pivotal
studies. Therefore, we think that the response may depend on the extent
and depth of curettage. This was discussed by Dr. Alosh, that efficacy
shows center dependence and there was a high curette-vehicle-PDT
response.

This is an example of curettage, of lesion preparation provided in your
briefing package by PhotoCure on page 124. This patient, however, was
not studied in the pivotal studies, not in studies 307 or 308. It
appears from the photograph here that the lesion preparation appears
rather extensive. During conduct of the clinical trials, most patients
did not receive local anesthetics. However, according to concomitant
medications for this patient, Xylocaine spray and Xylocaine was listed
as a concomitant medication, but I\'m not sure at what point or when any
of that medication was used.

Recurrence data is a part of efficacy for the treatment of basal cell
carcinoma. In the context of discussing the pivotal studies, since all
lesions would have been excised, the agency and PhotoCure discussed the
recurrence data for nodular BCC. PhotoCure agreed to provide a minimum
of 250 subjects to be submitted. We requested a 2-year follow-up at NDA
submission and that patients be followed up 5 years post-treatment as a
phase IV agreement.

What was submitted was PhotoCure provided 2-year recurrence data on 46
patients with 47 lesions with primary nodular BCC treated with
curette-MAL-PDT from a study that you\'ve heard about, study 303, which
was a phase III randomized, open-label study versus one surgical
excision.

In an attempt to have a larger database, we also looked at study 205,
which was a phase II non-randomized, open-label study that included both
nodular ‑‑ there were 38 lesions and superficial lesions, 39 lesions.
There were other patients, 3 or 4 lesions, considered
nodular/superficial. However, the focus will be primarily on nodular
BCC, and I will discuss later the problems that we find with including
these patients with the database for the primary nodular.

Recurrence is based on clinical assessment, inspection and palpation,
and in some cases confirmed by punch biopsy when the lesion is
clinically positive for recurrence. Treated areas that were apparently
clinically clear were not biopsied and are being followed.

Study 303 that you\'ve heard about was a European randomized,
open-label, multi-center study in 101 subjects. There were 52 patients
randomized to the curette-MAL-PDT study arm and 49 patients randomized
to the surgical treatment arm. The initial post-treatment assessment was
at 3 months, and patients were followed 12 to 24 months for clinical
recurrence.

The surgical excision study arm underwent one excision. As previously
mentioned, the surgical excision margin was standardized at 5
millimeters. However, the range was from 1 to 5 millimeters, and I
believe a mean of ‑‑ PhotoCure can give you that. I think it was a mean
of somewhere around the neighborhood of 5. However, the histology
indicating whether the borders ‑‑ whether there was involvement of the
lesions with BCC cells was not submitted to the agency for review.

Additionally, we\'re using this for recurrence data. The recurrence data
protocol was embedded in the original study protocol and the follow-up
procedures are minimally described.

This patient was provided by PhotoCure on page 100 of your briefing
document, and it is given as an example of complete response. This
patient is problematic in that it is difficult sometimes to evaluate
responses based on photographic data. For example, in the second
photograph here, the distance is further away and there\'s a light
shining here on the area. So it makes it difficult to really assess the
area that was treated. Nonetheless, this patient does appear to have a
clinical response and a relatively good cosmesis from the treatment.

This patient also represents problems with early clinical assessment
because this patient was discontinued 3 months after this evaluation
with a recurrent lesion. This patient also presents a problem, and we\'d
like your discussion about how to handle recurrence data for
discontinued patients and missing data.

Recurrence will be discussed in terms of lesion recurrence because some
patients had more than 1 lesion, although some had 1 lesion. Also for
study 205, some patients had both types of lesions, both nodular and
superficial.

So we looked at the recurrence data in two different ways. We looked at
recurrent lesions and for study 303, the MAL-PDT treated arm had 1
recurrence within 6 months and 3 ‑‑ and this is a little bit different
from the sponsor right here, but they had 3 at 12 months. And for the
24-month recurrence, we have 4 lesions for a 9 percent recurrence rate.

If we look at the missing data, we have 12 additional lesions that were
missing from the 24-month MAL arm. If we add the 12 to the 4
recurrences, we get a recurrence rate of 34 percent, and the confidence
intervals are given here. So depending on how you handle the missing
data, recurrence rates based on clinical observation can range from 9
percent up to 34 percent or as low as 2 percent and as high as 49
percent.

For the surgery treated arm, the recurrence data was assessed the same.
At 6 months, there was no recurrence. At 12 months, there was 1 lesion
missing, so we added that in. So that gave us a 2 percent recurrence
rate. So at 24 months, the recurrence rate for the surgical arm was 2
percent, and if we added the missing data, there were 7 lesions missing.
Added to the 1 recurrence, it gives us a total of 16 percent. So for the
surgical treatment arm, depending on how you handle the missing data,
you can have recurrence rates from either 0 percent or up to 29 percent.

We also looked at a failure-to-cure analysis. For failure-to-cure, we
looked at the initial failures to treatment, or treatment failures, plus
recurrences, and then we added in the missing data, depending on how you
want to handle the missing data. At 6 months, there were 9 out of 56 ‑‑
we\'re still talking about lesions here ‑‑ 16 percent. At the 12-month
follow-up, there were an additional 12 missing lesions which gives us 21
percent. And if we add in the recurrent lesions of the 4 from the
recurrence data, we can get a failure-to-cure rate of up to 45 percent,
with a confidence interval of 31 to 59 percent.

The same approach was taken for the surgical treatment arm, and there
was a failure-to-cure over the total number of lesions. At 24 months,
including the missing data, the recurrence rate for surgery may have
been up to 16 percent.

The phase II recurrence study 205 was a non-randomized, open-label study
that included both nodular and superficial BCC patients. This study
included 57 patients with 79 lesions. They were evaluated for recurrence
up to 24 months. The sponsor presented additional recurrence data that
we have not had an opportunity yet to review for these patients
presented today.

There were 30 patients in this group with 38 nodular BCC lesions, and
there were also 3 patients with 1 superficial/nodular lesion with 1
lesion in the study. So there was recurrence data submitted at 6, 12,
and 24 months.

However, we have difficulty including these patients in with the primary
nodular in that the patient population was different. It was mentioned
that the criteria that was used for consideration of high-risk, and it
was also mentioned that one of the high-risk lesions, morpheaform, BCC
was not included in this patient population.

The written instructions were different, appearing to have curetting
below the epidermis.

There was a difference also in the application of the MAL cream to the
lesion border. In the pivotal studies, a 5-millimeter border was to be
applied, but for this study, the border was listed as 10 millimeters.

Also, there were different lamps used in some patients. I think
PhotoCure mentioned about 7 or 6 patients had used a different lamp.
However, as I previously mentioned, the use of the lamp is an integral
part of this application, and for patients with lesions that were 55
millimeters or above, up to 110, with use of a different lamp, it may
not be applicable to the study of primary nodular. Also listed in one of
the adverse events report, there was a second-degree burn listed for a
patient who had received treatment, application of MAL cream and use of
a different lamp.

However, we\'re presenting the data here for your consideration if you
deem these patients should be considered in the recurrence data
patients. For the agency\'s analysis with recurrent lesions plus missing
lesions ‑‑ this is taken at 24 months, recurrence data. For superficial
BCC, there was a 28 percent recurrence rate and the confidence intervals
are given here, as little as 15 or as high as 45 percent.

But primarily we\'re interested in the nodular. The nodular rate was 37
percent. It could be as low as 22 or as high as 54 percent. And if you
would like to include also the superficial/nodular patients, the numbers
were small and we have a 33 percent recurrence rate.

Now, one of the other difficulties with this study is that the study was
non-randomized and the study was subject to a review board, therefore
subjects and lesions were not included in the database. For example, the
patients that I showed you with the curettage in study 205, with
extensive curettage, there were a number of other lesions located on
this patient. However, only the large lesion was included. In the
superficial/nodular group, there was a patient who was followed out to
24 months and then discontinued from the study, stating that the patient
should not have been enrolled, although the patient had had
non-recurrence evaluations at 6 and 12 months.

So, in conclusion, the database consists of 46 patients or 79 patients,
depending on whether you want to include the 30 patients from study 205
and the 3 patients with the nodular/superficial lesions. From study 303,
there were only 46 with 2-year recurrence data.

The 2-year recurrence rate for MAL-PDT in patients ranged from 9 to 34
percent, depending on how missing data were accounted for, and the
failure to treat adequately rate was 45 percent at 2 years. And a larger
database was requested by the agency.

The cosmetic outcome has been assessed by PhotoCure, and in the pivotal
studies, vehicle patients had as good or a better cosmetic outcome than
the MAL treatment group, but poorer response with regard to treatment
outcome. However, the numbers were small.

Cosmetic outcome is considered secondary by the agency to non-recurrence
of basal cell cancer. Recurrences may ultimately result in a worse
cosmetic outcome due to the need for further treatment.

Assessment of cosmetic outcomes across treatments was not agreed upon
between PhotoCure and the agency.

Data from the pivotal studies will be presented on the next slide.
However, there are a limited number of patients in each study arm.

Photographic assessment was not provided to confirm the data. However,
you have to be careful with photographic assessment, making sure that
distance and lighting are as close as possible. The division did suggest
or recommend that cosmetic assessments could be made prior to surgical
excision in the pivotal studies and supported by blinded, independent
review of photographs.

This is based on PhotoCure\'s results for the pivotal studies for the
cosmetic outcome. However, in this study results are not consistent
across the two pivotal studies. It was only the investigators in study
308 that rated the excellent response rates, when we\'re looking at the
excellent response rate, higher than the vehicle response rates. In the
U.S. study, they were both about the same.

Patient assessment differed in the excellent category from the
investigators in that the patients rated their cosmetic response rate
higher than the investigator in the vehicle group in both studies.
However, the results of their BCC being present was not known at this
time.

As previously mentioned, there have been no systemic local effects
identified from the adverse events reported and the laboratory
monitoring. As PhotoCure pointed out, the adverse events were reported
as local and non-local and that local did not mean treatment site
reaction. It was not confined to treatment site reaction but was based
on WHO classification of skin and appendages.

Someone had asked about blinding. In the pivotal studies, the
investigators applied the cream and the study nurse applied the
illumination to monitor blinding. The study nurses also recorded the
adverse events.

The local adverse events that were reported were pain, burning, and
stinging, and the phototoxic signs were erythema and edema. And there is
a high contact sensitization rate. High contact sensitization has been
demonstrated to MAL cream.

The local adverse events, as previously mentioned, consisted of skin
pain, skin burning, skin stinging. The results are higher in the active
group as opposed to the vehicle group. The sponsor has given you a
summary of those adverse events.

Additionally, the adverse event severity was reported as moderate to
mild in the pivotal studies.

The local adverse events in the open-label studies also recorded a high
incidence of pain, burning, and stinging skin. However, the intensity of
the reaction was different in that there were reports of severe pain,
burning, and stinging. It was mentioned that 1 patient was hospitalized
due to severe pain and treated with morphine.

So patients treated with curette-MAL-PDT could have skin ulcerations and
blisters that could last 1 to 2 weeks after treatment, and in two cases
erythema that lasted up to a year. Now, this was obtained from the
non-U.S. labeling. The drug is marketed in Europe. Therefore, no
separate analysis for these recurrences are available from the agency.
And some of these came from the integrated summary of safety.

Curette-MAL-PDT was associated with a higher incidence of pain, burning,
or stinging than curette. The use of anesthesia with MAL-PDT treatment
was not studied in a systematic fashion. In fact, there were only 26 of
the 538 patients studied who used local anesthesia. So, therefore,
there\'s minimal instructions for the use of anesthesia, and from the
proposed label insert, tumor fragments from most lesions may be removed
without damaging normal skin and without the use of anesthetics.

A dermal sensitization study was performed, and these studies are
generally routine with topical products that are applied. It is a study
that is conducted in normal human volunteers. Sensitization was
demonstrated in the dermal safety study.

There were 2 patients during the clinical trials that reported
urticaria/hypersensitivity reactions, and from post-marketing there have
been 2 patients with allergic reactions and 1 of them was a positive
rechallenge.

I would also like to state that during the collection of adverse events
during the clinical studies, the data were not collected in a fashion
that we could tease out adverse events due to curetting, to the cream
application, or to the illumination. So, therefore, we cannot say
whether or not there were any incidents or suspicion of sensitization
due to MAL cream.

The sensitization study design was as follows. There was an induction
phase in which MAL and MAL vehicle were applied for 3 weeks. There was a
2-week rest period. Then there was a challenge phase. Now, the challenge
phase was a little different in that there was only a 3-hour application
of MAL cream and MAL vehicle applied, and there was a 48-hour
application time for the aminolevulinate .1 percent cream in soft
paraffin and the vehicle for a cross-sensitization challenge.

For the dermal safety study, there were 215 planned. According to the
amendment, after 156 patients were included, the other patients were not
studied due to reactions suggesting sensitization in half of the first
102 patients who had been tested. Out of the 156 that were included in
the study, there were 58 dropouts, and these patients may have already
been sensitized. There were 98 who agreed to continue to the challenge
phase.

In the challenge phase, there were 40 patients who refused to have MAL
cream applied and there were 58 patients who were challenged with MAL
cream. So out of the 58 who were challenged with the MAL cream, there
were 30 that were considered positive. There were 3 that were considered
equivocal, and there were 25 negative. So from this study in normal
human volunteers at least up to 52 percent of the 58 subjects, not
counting the 58 who dropped out, who continued and did not refuse to
have MAL cream applied, were sensitized to MAL cream.

The ALA 48-hour cross-sensitization challenge was tested in 98 patients.
Out of this group, none were judged positive to .1 percent ALA. 2
percent were judged with equivocal reactions to ALA, and 2 percent were
judged positive to soft yellow paraffin vehicle that was used for the
ALA.

So in conclusion, MAL cream has an unusually high contact sensitization
potential of at least a 52 percent sensitization rate in a provocative
study. Cross-sensitization to ALA, an endogenous substance, cannot be
ruled out by this study that was conducted. And sensitization of MAL
cream of health care workers and of patients are of concern.

In summary, the curette-MAL-PDT has been shown to be statistically
superior to curette-vehicle-PDT for the chosen outcome assessment in the
pivotal studies, and we are asking the committee to consider the
adequacy of these studies for estimating the treatment effect based on
the early histology and the small number of patients studied in the
pivotal studies, the minimal recurrence rate data for primary nodular
BCC that was submitted.

We\'d also like for you to discuss the adequacy of instructions for
lesion preparation due to an apparent high vehicle-PDT response rate and
a wide center-to-center variability.

A numerically higher recurrence rate with MAL versus surgery in one
small open-label study was seen. The exact point estimate is uncertain.

For safety, we would like for you to discuss pain and minimal
information regarding anesthesia and pain control since anesthesia was
not systematically studied and pain could range from moderate to severe,
and also the unusually high contact sensitization rate seen in the study
conducted.

This is an example of the CureLight lamp which is an integral part of
this application.

DR. STERN: Thank you very much.

What I\'d like to do is first start with questions to the agency about
their presentation, and if we\'ve concluded those specific questions,
then we may have more general questions starting before lunch, if
there\'s time, but until we\'ve completed questions about the
presentation, it should be strictly for the agency at this time.

Dr. Plott?

DR. PLOTT: Dr. Vaughan, I wonder if you would answer a question. After
the agency gave the sponsor direction for an endpoint of clinical and
histologic cure as their primary endpoint, they chose to go on to just
look at histology. Could you explain the agency\'s position for choosing
that combined endpoint, and why is that important? And is that
consistent with other applications of other products that are being
looked at that might combine clinical and laboratory endpoints?

DR. LUKE: With regard to basal cell carcinoma, which is a tumor, a
clinical response is thought to give you a preliminary survey of whether
there is tumor there or not and followed by a histologic evaluation of
whether, indeed, there are tumor cells present, knowing that you knew at
one point there were already tumor cells from the initial biopsy. This
is the rationale for obtaining both a clinical and a histological
endpoint.

DR. KATZ: A question to Dr. Hansson. Dr. Hansson, the first clinical
photo you showed a person with basal cell on the nose previously treated
with Mohs.

DR. STERN: I\'m sorry. We shouldn\'t go to the sponsor until we\'ve
finished the questions for the FDA.

DR. KATZ: Oh, I thought we were asking actual questions.

DR. STERN: No. I\'m sorry. First, the questions for the FDA
presentation, and then we\'ll have questions for anyone. I\'m sorry.

DR. DRAKE: Dr. Vaughan, the missing data, the missing cases you rolled
into potentially active tumors. I\'m not sure how to ask this question,
but when we were doing guidelines for the American Academy of
Dermatology, what we found is a lot of these people disappear because
they\'re well because they don\'t have any more tumor. So did you also
roll the data in to assume these 40 had been cured and didn\'t need to
come back? I mean, you certainly rolled them in because you made the
assumption they might not be cured. Did you look at it in the reverse
manner too?

DR. VAUGHAN: Yes. Actually that\'s how PhotoCure approached the
recurrence data. The missing patients were not included. Therefore, we
have rates with the missing data, without the missing data, and
per-protocol recurrence rates.

DR. STERN: Lynn, they were in the column before that very last. They
were in the top of the last column, the simple proportion ‑‑

DR. DRAKE: I know what the sponsor did.

DR. STERN: No, no. In her presentation. If you could go back to that
slide.

DR. DRAKE: Well, I misunderstood then because it impressed me that she
had what was real and then she rolled in the missing as active lesions.
And I want to know what if she rolled them in as a successfully treated
lesion.

DR. STERN: She did that on the top number.

DR. VAUGHAN: It would be the recurrence. We gave two ‑‑

DR. KATZ: 9 percent.

DR. DRAKE: So the 9 percent included? I remember the 9 percent number.
You assumed that all the missing data was cured?

DR. VAUGHAN: Slide 16.

DR. DRAKE: I want her to answer it, Rob.

DR. VAUGHAN: Which slide are you referring to? Slide 32? Sorry. Slide
32, page 16, slide 32.

DR. DRAKE: I remember the slide. I know exactly the slide.

DR. VAUGHAN: The top number will give you the number of actual clinical
recurrences.

DR. DRAKE: That\'s actual. Then you took the missing data and you
assumed that they were bad.

DR. VAUGHAN: So, therefore, if it wasn\'t reported as recurrent, then it
wasn\'t counted as a bad outcome.

DR. DRAKE: But it also wasn\'t counted as a positive outcome. In other
words, if you added all those missing cases to the actual lesions, you
would have an improvement in the outcome.

DR. STERN: If you look, the denominator for both the ‑‑ it\'s 4 over 47
people in the trial. That\'s the number of tumors over the number of
people or lesions. I\'ve forgotten which.

DR. VAUGHAN: Lesions.

DR. STERN: 9 percent. That\'s your conservative assumption that
everybody who didn\'t come back was cured. And the lower one is the 16
over 47 assuming everybody that didn\'t come back had a tumor. The
denominators are the same.

DR. DRAKE: Got you. Thank you very much.

DR. STERN: To me what\'s interesting in looking at these data is the
differential in the number of people who did not return. I think a
conservative assumption is to assume that the difference in the
non-returnees are the unhappy people who went elsewhere. So, for
example, if you have symmetrical not follow-up, then you\'d say, well,
it\'s probably equal reasons in each or you could project the rates
forward using the smaller denominators, a whole variety of ways.

But if you look at these data, what interested me is ‑‑ and I\'ve
forgotten the exact numbers. I think it was 12 versus 8 or 12 versus 7.
So the question is why should a higher proportion, 12 out of 47 versus 7
out of 51, decide not to come back. I think in a lot of studies, when
you\'re trying to do certain endpoints, you really look at that
difference in failure to follow-up as a signal for why didn\'t they come
back since it\'s a randomized study at the beginning.

DR. DRAKE: Well, Rob, I understand what you\'re saying. I understand
what you\'re telling me about the denominator, but to assume that people
don\'t come back because they\'re unhappy is, I think, an incorrect
assumption because, for starters, if you look at the cosmetic results,
the patients were far happier with the cosmetic results from this
treatment and from curetting than they were from surgery. So it could be
they didn\'t come back because they were very happy with the cosmetic
result whereas the surgical patients came back more because they were
unhappy about the scars. So I don\'t think you can make that assumption.
People don\'t come back and the fact of the matter is we have no idea
why they don\'t come back.

DR. KATZ: Since we\'re discussing page 16, this slide, we really
shouldn\'t confuse things with cosmetic and cure rate. Let\'s compare
apples and apples. Assuming the company\'s data of everybody cleared up
that didn\'t come back, you\'ve got more than four times as many
recurrences percentage-wise in the MAL group as in the surgery group.
Four times as much. This is with 2-year follow-up; 9 percent recurrence
at 2 years with the already intuitive data that we have with 5-year
follow-up with surgery with a recurrence rate of less than 5 percent.

It\'s counterintuitive to assume that all those folks didn\'t come back
in the MAL group because they were cured when we know from the early
studies described that only 47 percent over placebo were cured at 6
months or 3 months or whenever that was. So to assume that these other
folks, these 16 people, didn\'t come back because they were cured, when
we already know from the previous studies that only 47 percent are cured
at the 6-month follow-up, it\'s quite counterintuitive.

DR. STERN: I\'m sorry. Dr. King.

DR. KING: I still come back to the question the agency is going to ask,
I think, which is what is the potential for complications with the
people who apply it, the health care workers, and how do you do
prescreening to find out who may be unusually phototoxic. To put
somebody in the hospital at Vanderbilt for applying light requiring
morphine, et cetera, gets you a line of lawyers you won\'t believe. So I
think that I\'m looking for some direction of what the agency is looking
for that we should examine for instructions.

DR. WILKIN: Well, I think there are two pieces to this. The first piece
is that it\'s difficult in the clinical study setting, outside of a
dermal sensitization study in normal subjects, to actually be thinking
about the difference between phototoxicity and contact
hypersensitization. The skin has a limited repertoire in acting against
noxious substances: erythema, blistering, those sorts of things. It\'s
difficult sometimes to tease out exactly what the causal mechanism might
be.

On the other hand, the provocative dermal sensitization study says that
it has the potential to have sensitization. That\'s what we learn from
those dermal kinds of studies.

The concern is for both patients who ‑‑ if someone has a basal cell,
it\'s very likely that they\'re going to have a basal cell carcinoma in
the future. But the staff at a treatment site would presumably have much
greater exposure. I think it\'s interesting that the sponsor has not
found this to be a problem. So we have the apparent absence of a problem
in real practice, but in a provocative study which is sort of an
intense, provocative way of finding out if there\'s any potential, it\'s
telling us a different sort of thing. So part of our question for the
committee is to try to put that together and give some feedback.

DR. STERN: Dr. Ringel.

DR. RINGEL: I\'m going to try not to get lost in terminology, which I
find myself doing. The recurrence rate and the failure rate. I take it
that the recurrence rate only applies to people who at 3 months had a
complete response, and then you followed them for a recurrence rate.
Whereas, a failure rate really is trying to say who didn\'t respond to
this treatment at the point you\'re looking at them.

DR. VAUGHAN: Yes, that\'s how the data was assessed.

DR. RINGEL: It\'s odd because with surgery, if we\'re talking about a
recurrence rate, if you look at someone 3 months post-op, you\'re just
going to say they recurred; whereas with this study, if they didn\'t
respond, you\'re not even considering those.

I guess what I\'m saying is why ever are we looking at recurrence rates
at all? It seems to me we should only be considering failure rates. What
I want to know when I\'m treating someone is they have a basal cell
carcinoma at point 0, 2 years from now, what\'s the likelihood of their
having basal cell carcinoma. And that\'s the failure rate, not the
recurrence rate, it seems to me.

DR. VAUGHAN: Could you put up slide 33 please?

Let me understand your question again. The last part of your question
again is why are we concerned about the recurrence rate 2 years later?

DR. RINGEL: Yes.

DR. VAUGHAN: Because basal cell cancers are looked at in terms of cure,
as Dr. Stern mentioned earlier today, in terms of years. 5 years is
short-term. Beyond 5 years is long-term. So we want to follow that as an
integral part of efficacy. Generally you treat a patient and you bring
them back 6 months to a year for follow-up, but it was the design of
this study to bring patients back at 3 months to assess whether
additional treatment is needed.

DR. RINGEL: I understand why it\'s a long-term study. What I don\'t
understand is why we need to characterize that long-term study in terms
of recurrence rates which seems to leave out a part of the population
which was initially treated. If you\'re really doing an intent-to-treat,
you will take a look at the entire population which is your failure
rate.

DR. VAUGHAN: Well, that\'s what the failure rate does.

DR. RINGEL: Yes. I think that we should be focusing on this slide rather
than the recurrence rate slide. That\'s what I\'m saying.

DR. STERN: Dr. Tan.

DR. TAN: Yes. We talk about the study has a very small sample size. I
just have a simple question I\'m curious about. Was the randomized trial
designed with detecting a 30 percent difference and if the trial was
conducted in a way following the protocol, originally designed?

DR. ALOSH: Yes, as I mentioned we have this communication between the
sponsor and the agency about the design of the trial. The study was
designed to give comment about the endpoint, and the power of the study
would be related, as you know, to the endpoint which you are assessing.
So we gave the endpoint. The endpoint should be clinical as well as
histological evaluation, but even though those comments ‑‑ they were on
March 7, 2000 ‑‑ the sponsor and the protocol in August maintained to
have histology. So this is why I think the efficacy result wasn\'t the
same if you look to histology alone versus histology and the clinical
evaluation which was requested by the agency.

DR. TAN: So the trial was designed to detect probably a 30 percent
difference in response rate. So, therefore, the trial was designed as
having 30-some patients in each arm.

DR. ALOSH: That\'s right. I think there is communication. Probably the
sponsor could provide more detail, but I think the issue of powering the
studies really are related to the endpoint, and what we feel between the
sponsor and the agency, we did not have the same endpoint. We gave
comment, again as I said, clinical and histology, but we got something
back in terms of histology alone.

DR. STERN: Could you just clarify your response? I had thought I saw a
slide where the agency made a specific recommendation about sample size
for evaluation of nodular which was different than I think I understand
the number of analyzable cases that have been presented today. Could you
refresh our memory? I had thought there was some number like 250 that
you were asking for ‑‑ that the agency suggested, I should say, in terms
of powering the study.

DR. WILKIN: Actually that was in terms of recurrence data. It wasn\'t
with the two pivotal ‑‑ that\'s right. The randomized.

I think Dr. Clementi accurately, in his slide 15, documented the
division/sponsor meetings where we did have a lot of communication.
There was a pre-IND meeting in August of 1999, a phase II meeting in
March of 2000, a pre-NDA meeting June of 2002.

I would say if you look in, again, the CFR, Code of Federal Regulations
at section 312.47, it talks about meetings between FDA and sponsors. It
emphasizes the need for good communications and it also mentions a
pivotal meeting is the end-of-phase II meeting.

We did have, I think, in addition to what Dr. Clementi is listing, a
teleconference that did focus on some aspects of basal cell carcinoma in
addition. So I think there\'s even one more where we got to spend some
time together.

Then if you look in 312.47, it talks about if one comes to the very end
at the pre-NDA meeting, normally that\'s a meeting where the sponsor and
the agency groups meet and they talk about format and content, what
should be in the NDA, how it should be organized so that our review team
can very efficiently get into it and review the data. But in the regs,
it also speaks to any additional aspects that haven\'t been closed on
should be discussed at that time. I think that that was a fairly
substantive meeting in terms of identifying those additional sorts of
things.

I have no doubt the sponsor believes that they have addressed the spirit
of what the agency has asked for. On the other hand, it\'s not quite the
same thing as having an end-of-phase II kind of an agreement which we
are able to achieve in some circumstances. So I don\'t want to make too
much of this. I\'m just saying I think they heard advice and then made
some decisions as to what they thought would be compelling, and when the
NDA came in, we looked at the NDA and we frankly thought that there was
sufficient information to file it and review it and consider this.

DR. TEN HAVE: I have a question for Dr. Alosh in terms of the
variability of outcome for the two cycles of treatment. Correct me if
I\'m wrong, but it appears that most of the variability is in the
outcome in the first cycle, but when you consider both the first and
second cycles, there\'s less variability across the centers. If that is
an accurate summary of what you were presenting and given all the
problems with the study design looking at the first cycle and looking at
outcomes in the first cycle given that some of the partial responders
are then treated subsequently, can you re-explain your rationale for
focusing on the first cycle in spite of those problems and given that
there seem to be less problems with variability across center for the
first and second cycles? Does that make sense?

DR. ALOSH: Well, I agree. This is study 307. All right. For the first
cycle, really the interaction was there, and I think I stated that this
wasn\'t the primary endpoint to have the first cycle. However, we felt
data from the first cycle, it\'s the largest ‑‑ to include the largest
number of lesions to be analyzed, because everyone is treated once. What
we have, the number of lesions I think which went through the second
cycle, roughly I\'d say around 10. I don\'t have the exact number.

But I agree and I stated this. I thought the interaction is significant
only for the first cycle. If you look to the first and second cycle
combined, the Breslow data still gives you a p value of .134, which is
not significant. We judge it by the p value, as you know, .10. So it\'s
close.

But I think the point here, if you look to the last two columns, the
Breslow-Day test gives you .31, and this is based on histological
evaluation only, which is the endpoint the sponsor analyzed. So the
point here, you could see the center-by- treatment interaction, the
magnitude of that, it depends on how the endpoints are evaluated. If you
consider histology alone, you could see there is no significant
treatment-by-center interaction, .3 compared to .1. If you consider
clinical and histological, you see .13, which is close to the .1. I
agree. Interaction is really for the first cycle. I want to emphasize
that this is the biggest set.

DR. STERN: So let us now go on to questions to both the sponsor and the
FDA with any parts of the application. Michael?

DR. BIGBY: This question is to the sponsor. Can you put up your table
37? It\'s section 7.2.1.5.1 in your book. It\'s table 37. This is with
regard to studies 307 and 308.

Just sort of as a background, the reason for doing a placebo-controlled
trial is to separate the treatment effect of the active treatment versus
all the nonspecific things that go on in a trial. And efficacy is
usually measured based on the difference between active treatment and
placebo. The disturbing thing from this table is that if you look at
that column, the difference in both of the studies is either 42 or 48
percent and the confidence interval goes from 18 to 72 percent. So that
really is the treatment effect, not 76 or 77 percent. The real treatment
effect is the difference between placebo and MAL-PDT.

I just wanted to know the sponsor\'s response to a 95 percent confidence
interval of the actual treatment effect being, one, that wide and also
that potentially low so that could have a treatment effect of this
treatment as low as 18 percent if you looked at the 95 percent
confidence interval.

DR. MORRIS: I\'m Hilde Morris. I\'m the Director of Clinical Research at
PhotoCure.

I think you have to look at the treatment as a whole. It consists not
only of the cream. It consists of the preparation procedure, the
application of the cream, and the illumination, and you can\'t really
take out one of those parts of the treatment. So when we did our
vehicle-controlled studies, we had all the other elements. So you can
say that the part of the treatment that\'s attributable to the active
substance in the cream is what you are pointing out here, but in fact,
the efficacy of MAL-PDT includes all of the parts of the treatment.

DR. BIGBY: I have to say that I sort of disagree with that entirely and
that you\'re not trying to market just the light or just the curettage.
You\'re trying to market MAL-PDT. And if you do a placebo-controlled
trial, the actual treatment effect is that which is different from your
control. Now, you can argue that you picked the wrong control, but you
can\'t say that you do a placebo-controlled trial and not want to accept
the difference in the treatment as the real treatment effect. I mean,
that\'s just sort of the basic principle of doing controlled trials.

Another question. Table 42.

DR. KATZ: What page?

DR. BIGBY: Page 95.

So this was the versus surgery estimate. Just one clarification
question. In the ITT analysis down at the bottom, when you look at the
difference, you wrote an \"N/A\" under ITT. Why is that N/A? In the ITT
analysis, when you look at the estimate of the difference between
surgery and MAL-PDT, there\'s an N/A under ITT analysis, and I wondered
why that\'s there.

DR. MORRIS: The primary analysis in this study was the per-protocol
analysis, as we discussed also with the FDA since that\'s the most
conservative way of looking at a non-inferiority trial.

DR. BIGBY: Absolutely not. It\'s just the opposite. The ITT analysis is
the most conservative way. So why is that an N/A?

DR. MORRIS: Not for the non-inferiority trials.

Maybe you want to say something, Per Fuglerud, our statistician.

DR. 8: Yes. I think I don\'t totally agree with you that the
intention-to-treat is the most conservative comparison when you want to
show non-inferiority because in an intention-to-treat population you
include all patients and that could reduce the difference between the
two treatments. And a more conservative way will be only to use the
per-protocol population because that will not reduce the difference
between the treatments.

DR. BIGBY: Okay. Well, is it possible for you by the end of the day to
fill in that number?

DR. 8: Yes. It\'s 14.6.

DR. BIGBY: So it\'s 14.6 percent.

DR. 8: That\'s correct.

DR. BIGBY: Thank you.

And then the confidence interval is what?

DR. 8: Sorry?

DR. BIGBY: The confidence interval of the number is what?

DR. 8: That\'s the lower confidence limit. I think we also have the
upper. We will bring it to you during the day.

DR. BIGBY: So this is my question, though. You say what you would have
accepted was an upper 97.5 confidence interval was less than 15 percent.
This is a study that has a relatively small number of patients. So what
is the power of this study to actually demonstrate that difference?

DR. 8: 90 percent.

DR. BIGBY: 90?

DR. 8: Yes.

DR. STERN: Are you sure that with an alpha of .05, the beta type 2 error
is .1 with a study of this size with these rates? That seems like a heck
of a lot of power to exclude a 15 percent difference, but I didn\'t do
the calculations.

DR. 8: The calculation is described in the protocol and the power is 90
percent in this calculation.

DR. STERN: With about 50 people in each arm.

DR. 8: Yes.

DR. STERN: And the expected rate in the baseline was 5 percent in the
calculation and the comparator group ‑‑

DR. 8: We expect a response of surgery of 92.5 percent, a complete
response rate, and we assumed that model was the same.

DR. STERN: And you were 90 percent confident that if the real rate
difference was 15 percent, you would detect that in a 50/50 study.

DR. 8: With a 90 percent power, yes.

DR. MORRIS: Can I say something about the interpretation of this study
because I think we all agree that although it does end on the right side
of the statistical significance here, it is borderline at this 3-month
assessment time point. I think we do realize that the difference
increases over time, and we have said in our conclusions that the
response rate for MAL-PDT is slightly lower than surgery, at least when
you look over time. However, we believe that in a risk-benefit
assessment, that there are other aspects of the treatment that can make
it a useful tool in some patients.

DR. BIGBY: I\'ve got a couple more. Page 110. This is a procedural
question. The description of cryotherapy is rather brief, and it
basically said it was done for a minimum of 20 seconds and there were
two cycles. Do you have the data about what was the range and median and
maximum for cryotherapy and it how it was determined how long to freeze
a lesion?

DR. 8: Can you please repeat the question?

DR. BIGBY: The only thing that you said about cryotherapy was that it
was a minimum of 20 seconds. Now, having treated many basal cells with
cryotherapy, I\'ve never treated anybody with as little as 20 seconds.
So what I want to know is what was the range of cryotherapeutic
treatments, the median and the maximum, and how was it determined how
long to freeze things.

My skeptical reaction to this study is that what you\'ve shown in this
study is that MAL-PDT is more effective than sort of inadequate
cryotherapy.

DR. STERN: And I guess the other question is if the cryotherapy were
adequate, how can these recurrence or failure rates be so much higher
than any of the published data for the type of lesions that you\'ve
treated not for canthal lesions or very severe sites, but of the type of
lesions you\'ve treated, the whole literature would suggest a fraction
of this recurrence rate. So in fact there\'s consistency between what at
least Michael and I learned as the adequate treatment with cryosurgery,
what we would consider inadequate by our clinical standards at a higher
recurrence rate than published in the literature.

DR. MORRIS: On our side, 67 in the presentation today, we had the
specification of the cryotherapy. They were supposed to freeze until
they obtained a rim zone of 3 millimeters around the lesion and then to
thaw, and the thaw time was to be two to three times the freeze time,
and then a repeat freeze session. So that was how that was described.

I think that when you look at our data compared to what is in the
literature, our data is prospective and randomized data, and in the
literature, I think you only find studies that are retrospective, and
they will invariably have different response rates than a well-designed,
controlled study.

We\'ve seen that in our AK studies too where we also compared to
cryotherapy, and again, cryotherapy had also in those studies much lower
response rates than the retrospective studies in the literature would
indicate. There are no studies that have prospectively compared
cryotherapy to other treatments in AK and multi-center.

DR. BIGBY: Okay, but do you have recorded what the range, median and
maximum, was for cryotherapy?

DR. MORRIS: Yes, we do have those numbers, but I\'d have to go find them
for you and I can get them during the day today.

DR. BIGBY: I have just two more. With this question of sensitization,
have the patients who had standard MAL-PDT treatment, two sessions and
then another two sessions 3 months later if they had partial response,
been patch-tested to see if they are sensitized to MAL?

DR. MORRIS: No, they have not been.

DR. BIGBY: So you don\'t actually know if in normal use the patients get
sensitized to MAL.

DR. MORRIS: No. Maybe you want to talk about these cases.

DR. POSNER: You\'re correct. We do not know what the incidence of
contact sensitization is. What one can say, however, is that it hasn\'t
been a clinical problem. Perhaps a suspected case has not been a
difficult problem to manage and certainly investigators haven\'t found
this as an issue. We are talking, of course, about contact dermatitis
and nothing worse.

DR. STERN: I don\'t know how you would tell that. The only time that
these people are exposed are at the time they\'re also getting light,
which would give them an erythema and blistering reaction that at least
I would challenge anyone to tell whether there was also a contact
dermatitis going on. The only way you could test for sensitization in
any clinically meaningful way would be a subsequent rechallenge on a
distant site away from the treated area.

So the fact that no one reported it ‑‑ sure, it\'s hard to tell a
contact reaction after someone has had a severe phototoxic reaction in
the site. I just don\'t think you could tell which was which and one
would reasonably suspect that it was a phototoxic reaction which is part
of the therapy and you couldn\'t separate them.

DR. PARISER: Let me just say that in routine use of this in the trials,
the use of the modality in the trials, I think you possibly could tell
under an occlusive patch test, if you will, considering the application
to be an occlusive test. The patients routinely and regularly had these
burning and skin sensitization ‑‑ not sensitization ‑‑ skin burning,
crusting, a little oozing. That was normal. A rip-roaring contact
dermatitis under a patch for 3 hours could have, not always, made some
kind of difference. There didn\'t seem to be a subgroup of patients
where that happened.

DR. STERN: I live in an area surrounded by poison ivy, and a far smaller
proportion of poison ivy reactions display what\'s described for oozing,
crusting, and blistering with the phototoxic reactions. So again,
perhaps you could detect them, but I would be clinically challenged in
being able to differentiate those in the clinical setting of this
therapy. It don\'t make sense to me.

DR. PARISER: I\'m not saying you can. But what if you put poison ivy
under a patch for 3 hours? It does make a difference I think.

DR. LUKE: Just to be helpful, we\'re looking at page 157 of the
sponsor\'s briefing packet. There are two cases that you\'re discussing,
the two so-called eczemas. One patient had eczema on the face and the
other patient had acute eczema. Both of those were thought to be
possibly suggestive of relationship to the product. In one case there
was a hypersensitivity test performed by an astute dermatologist which
reviewed sensitivity to both ALA, the endogenous substance, and MAL
cream.

DR. BIGBY: This is my last one. Page 125.

DR. POSNER: Sorry. Could I just clarify one issue there? The patient had
also been treated with ALA at a different site and was positive when
initially tested, but when they came back 6 weeks later, the response
was really negative except a very weak response to a very high
concentration of ALA, but undoubtedly a positive reaction to MAL. So
that is the one confirmed case that, as you say, the astute physician
did test with patch test.

DR. BIGBY: This is my last one. Page 125, the patient that\'s shown
there. When was he treated and what\'s his current status?

DR. MURRELL: This patient was from Dr. Vinciullo\'s center in Perth, and
my understanding from the sponsor and the data is that at 2 years
follow-up, which is the latest data that we have in the Australian
high-risk study, is that the patient is clinically negative. But we\'re
not doing biopsies at the 1-year follow-up because otherwise, there
would be no tumor left to keep on assessing by 5 years.

DR. DRAKE: Can I follow up on what she just said? Why would you want
tumor left to keep on assessing in 5 years? She just said there would be
no tumor left to keep on assessing. Why would you want tumor left?

DR. MURRELL: We don\'t want tumor left. What I meant was if we had done
biopsies on every single time we assessed the patient, you might have an
argument to say there was no recurrence because you had physically
removed it all.

DR. KING: Really probing the question of how do you know about
localization, in slide 6 it says there\'s minimum systemic uptake due to
low ability to cross the basal membrane. I don\'t believe that for a
minute, given the size of the porphyrin.

So I come back to you found that 160 milligrams per kilogram led to a
plateau. Is that possible like griseofulvin and other molecules the
epidermis is acting as a sponge? You\'re really just soaking up the MAL
and the fact it doesn\'t get through is more related you don\'t put on
too much, so you\'re not going to get much through.

You really didn\'t challenge the barrier in the usual sense. You\'re
just putting on MAL and saying what the absorption is into the
epidermis. To say it doesn\'t get through to the dermis or to the blood
vessels seems unbelievable to me.

DR. HANSSON: I agree. It sounded unbelievable to me as well. However, if
you look somewhere in this briefing document, the first observation that
really caused interest in this issue for us, before we did the
transepidermal in a cadaver for a type of skin test for objective
measurements, for some reason we found very, very low uptake of MAL
compared to ALA and to what other people have reported for ALA.

If you look at page 19 in the briefing document, the nude mouse is a
good friend of us because due to a very thin stratum corneum, they have
a fairly rapid exfoliation of the superficial cells and a similar high
proliferation of the basal cells to replace what is falling off.

We have been using the skin of the nude mice to test porphyrin buildup
and doing a lot of kinetic studies both with porphyrin formation and
porphyrin removal. One of the things we really discovered in the
mid-\'90s or early \'90s was that when we used aminolevulinic acid
derivatives where we have blocked the carboxy part of the molecule, the
buildup of fluorescence always only came at the site of location. If we
put the free carboxylic acid ‑‑ you have the picture to the left ‑‑ you
get some local buildup in the beginning, but very soon the whole mouse
became red.

If you go into our preclinical package ‑‑ I\'m too old to have a very
good memory, but I think the uptake in the skin patch test was something
like .06 microgram per square centimeter and a depot of approximately 3,
4, 5 percent of the total dose applied. It was a very high dose and the
systemic uptake from 4 grams ‑‑ was that correct ‑‑ was approximately
100 micrograms calculated.

If we did exactly the same thing for the free carboxylic acid ‑‑ or it
actually has been reviewed by the agency for another product for actinic
keratosis in this country. They have exactly the same test providing
figures which are 10 to 20 times higher that we get in exactly the same
studies.

So you say you would never have believed it, and I agree with you
completely. I would never have believed it. If you ask me for an
explanation, I would just say I really cannot provide it.

DR. KING: I still don\'t believe your explanation. It looks like a
thumbprint. Having worked with mice for about 15 years now, I know they
have a thicker skin or epidermis than the normal furred mouse. So when
you look at what you\'re looking at, you almost look like if you took
poison ivy and put it on there, in fact stopped. If it was stopped by
the basal membrane, it would be spreading out this way as opposed to
straight down type thing.

So I don\'t want to quibble a point, but I know you\'re saying it
doesn\'t penetrate very well, and I was suggesting that\'s what
happening is it\'s being selectively absorbed by keratin, something in
the cytosol or mitochondria only at that site. So that\'s why you get a
limitation. You\'re implying a barrier this way, but you don\'t explain
why it doesn\'t spread out this way.

So I like the poison ivy analogy, so I just wondered if you had an
explanation. Maybe if you did a subset or fractionization, you could
find out whether it\'s not only in the mitochondria but in the cytosol,
keratin, or other kinds of things different from ALA. Is that making
sense there?

You put a thumbprint. You get the chemical right there. Poison ivy. If
you put this on here and it doesn\'t go through like this, that\'s
different from saying you got stopped by the relatively permeable
basement membrane. That means it must have stuck to the type 4 collagen,
et cetera, et cetera. So you\'re now off into basic science, so I stop
right there.

DR. HANSSON: I probably agree with you except I didn\'t understand
everything you said. Perhaps the formulation that it doesn\'t seem to
penetrate the basal membrane may not be a good one. But when we do all
systemic measurements in all the organs, when you apply the free
carboxylic acid, after 8 or 12 or 24 hours most of it ends up in the
liver. If you do that with the derivatives, with a single carbon or a
6-carbon, nothing ends up in the liver. Honestly, I don\'t know the
explanation.

DR. KING: Sure, great.

DR. TEN HAVE: I have two questions clarifying some points that Dr. Bigby
raised for Dr. Alosh. One is a more general question about what the FDA
allows in the U.S. in terms of the primary analysis, whether it\'s an
intent-to-treat analysis or a per-protocol analysis.

The second question, I think which is more pertinent to this particular
presentation, is what is the threshold for inferiority deficits or
treatment deficits. The sponsor appears to be using 15 percent as a
clinically tolerable inferiority deficit in terms of 15 percentage
points. What does the FDA accept as a clinically tolerable inferiority
deficit?

DR. ALOSH: Thank you. I think, Dr. Ten Have, probably you are touching
on the non-inferiority trials, the European trials. In terms of those
trials, really the agency did not have input in terms of the protocol.
Those trials were completed before the sponsor came to the agency. So we
did not have much to say in terms of the non-inferiority margin.

I\'ll answer the two points which Dr. Ten Have phrased in sequence.

First, in terms of analysis, we used the ITT as well as the per-protocol
analysis. The statement that for non-inferiority trials we used the
per-protocol, it\'s conservative, myself, I do not agree with that
statement. I think the ICH-9 talked about a superiority trial to use the
ITT. It left it open in terms of the non-inferiority trials.

If you look to the European guidance, it talks about both of them, to
have the ITT as well as the per-protocol.

Lately in 2003, there is a paper in Statin Medicine which talks also
about having the two analyses. Consistently we have been asking for the
two analyses, the ITT and the per-protocol population.

The way I see it\'s conservative, only in terms of reduction in the
number of patients. Consequently you will end up with larger confidence
intervals. But what are the characteristics of those patients who are
dropouts from the ITT to reach to the per-protocol?

So this is really left to have been consistent in asking for the two
populations, for the ITT as well as the per-protocol, retrospective as I
said. We weren\'t consulted. The sponsor did not submit the protocol to
the agency for comments for those.

Concerning the second part about using a non-inferiority margin of 15
percent, it\'s really a clinical stat issue. In a way what\'s the margin
which you might think clinically could you do with that. But I\'d say
the stat part at least ‑‑ I mean, I leave it to clinicians to answer
whether the 15 percent is relevant or not. I\'m sorry. Do you want to
answer or should I just continue and then you could answer?

DR. MORRIS: I can just clarify how we reached the 15 percent. It was
agreed upon by the dermatologists who were the investigators in the
trial and it was a consensus among these dermatologists that 15 percent
was a difference that they would say was clinically relevant.

DR. ALOSH: That\'s fine. It\'s true you might agree with the
dermatologists, but I\'m stating what we do in the agency.

We have in the past some guidance. For the higher response rate, we\'ll
use a small non-inferiority margin. In particular, the response rate of
95 percent entire, we use 5 percent. If it is 90 percent entire, we used
to use 10 percent. Now, I\'ll go back. They were a few years ago and we
are not enforcing them now. But the message I think, the higher the
response rate, we\'d expect a smaller non-inferiority margin. And it\'s
also to discuss with the clinical to see how important it is.

There is another issue in open-label studies which is really gaining
momentum. There is no vehicle arm in those open-label studies, and
consequently, for the validity of those studies to be established, you
need to have the vehicle arm in those studies.

So from a statistical analysis point of view, I think we have several
concerns, I mean, about submitting was the patient population which Dr.
Ten Have tried to touch like the analysis for two populations. I think
the more serious is the non-inferiority margin. There is no vehicle arm.
So I don\'t know if I addressed your question. Thank you.

DR. STERN: I would suggest that after lunch the panel directly address
the issue of what difference in outcomes between accepted therapy and
the sponsor\'s therapy would be considered to be clinically meaningful.
In other words, do we agree that a 15 percent inferiority at the time of
measurement at 1 and 2 years is clinically, in fact, acceptable for a
therapy. I would suggest we just put that in our computers and not get
to it until after lunch because I think one of the things the agency
might want is our opinion about what\'s a meaningful difference in
outcomes as opposed to what the investigators might have said. So let\'s
not discuss it now but put it down on our agenda.

I think we have very quickly three more people to ask quick questions,
and we can always ask longer ones after lunch. Jimmy?

DR. SCHMIDT: I\'d like to ask a question to Professor Murrell. On page
107, in the study 304, you treated extremities. One of the banes of my
existence is these people who are coming in now with these superficial
basal cells on their lower extremities and also transplant patients. Can
you elaborate on what your results were with those patients? Were you
successful with the basal cells on the lower extremities? Because
there\'s no rate of whether they recurred or what happened.

DR. MURRELL: The 304 study wasn\'t one of the studies that I presented.
I presented the 310 and the 205, which were the uncontrolled studies.
Per, our statistician, is looking up to see what the subgroup analysis
for that particular location was because I don\'t know is the honest
answer.

But from the point of the view of the patients that I personally treated
with that, they did complete response. So they did well, but that\'s
just a small group of my own personal experience with those patients. So
we\'ll have to tell you later if you want specific numbers.

DR. SCHMIDT: Thank you.

DR. RINGEL: I had a bunch of questions, but I\'m just going to limit it
to one.

DR. STERN: Perhaps, if you have a bunch, maybe we should start with you
after lunch. Would that be acceptable to you?

DR. RINGEL: I could do one quickly now and then do the rest after lunch.

DR. STERN: Whichever.

DR. RINGEL: The kind of burning question I had, as I was reading this,
is I was imagining myself in front of the patient with a curette in my
hand and they say, curette it a little bit. And I\'ll tell you, I just
want to keep going. I really do. I just want to get rid of that sucker
right there.

(Laughter.)

DR. RINGEL: I guess the question is you\'ve compared it to surgery and
you\'ve compared it to cryosurgery. Why ever didn\'t you compare it to
electrodesiccation and curettage? It seems to me that if I had a chance
to electrodesiccate and curette a lesion twice and then have the patient
come back in 3 months and do it another two times, I think my cure rate
might have been pretty good. So I guess why didn\'t you use that as a
comparator?

DR. PARISER: Well, I really can\'t answer the question why didn\'t we
use it as a comparator.

But this is not therapeutic curettage that we\'re all used to in
curetting with the intent of cure. This is really debulking. It\'s
surface preparation. It in general requires no local anesthesia. It
sometimes doesn\'t even elicit much of any bleeding. So it\'s not
therapeutic curettage. The main reason why you don\'t want to keep going
is the patient is going to yell at you because he\'s not anesthetized.

Sure, a trial could be done and should be done of this procedure versus
curette and electrodesiccation, but that was not in the package.

DR. STERN: If it\'s okay, we\'ll break for lunch and continue with Dr.
Ringel and then Dr. Katz after lunch. We\'ll start back promptly at
1:00.

(Whereupon, at 12:10 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:02 p.m.)

DR. STERN: I\'d like to have everyone who would like to participate
please take a seat, and we will start opening the meeting for the open
public hearing. We have received no names at this point for anyone who
would like to present at the open public hearing. So this represents, as
they say in some places late at night, the final call or last call for
people who would like to participate and present in the open public
hearing.

(No response.)

DR. STERN: Going once. Going twice. The open public hearing is now over.

(Laughter.)

DR. STERN: Now we will continue to Dr. Steven Rotter who has been kind
enough to join us from Falls Church, Virginia where he is a
dermatologist in private practice and he will tell us more about his
background and training and talk to us about cold steel and Mohs
micrographic surgery and their efficacy in nodular basal cell carcinoma.

DR. ROTTER: Hello. Thanks for having me. My name is Steve Rotter. I do
skin surgery only in my practice. I specialize mostly in Mohs
micrographic surgery, but basically all skin surgery from laser down. So
I have experience with most of the treatment modalities for skin cancer,
although certainly not all.

I was asked to talk about Mohs micrographic surgery. I have a canned
lecture. I found out recently it should be a little bit different. So I
put some slides together that I\'ll show you and then I\'ll be available
for any questions that you have.

My training, if you want to know, is I was a resident with Kathy
O\'Connell at Hopkins and then I did a derm surgery fellowship at the
University of Pennsylvania. Before that, I did two years of general
surgery at Sinai Hospital, so I saw all kinds of ways to treat skin
lesions. The bias of my practice obviously is Mohs micrographic surgery.

I\'m going to fly through this very quickly because we only have a few
minutes. I\'m going to extremely quickly, and then I\'m going to stop at
a few points. Even after the end, there are some slides that I added in
here that you\'ll like and I have taken out some. I\'m going to explain
to you what Mohs micrographic surgery is. I\'m going to explain to you
about skin cancer.

Obviously, we all know there\'s a zillion cases of skin cancer in this
country. It\'s epidemic. 54,000-plus is the new estimate for melanoma.

We know why there\'s an increase. We\'re not exactly sure, but increased
sun habits and ozone. Obviously, history of radiation exposure, tanning
beds, ultraviolet light, et cetera, chemicals, farmers and people who
have exposures also get increased risk of skin cancer, also family
history.

Immunosuppression, chronic ulcers, virus, inherited diseases that make
you more susceptible, zero dermal pigmentosa, basal cell nevus syndrome,
et cetera.

Stop me if you have any questions at any time. I\'m just trying to get
to the main points for this which I think is comparing treatment
modalities of basal cell cancer.

We\'re talking about basal cells. That\'s the most common cancer. We see
1,500-plus of those a year in my practice. The most common location
unfortunately is the head and neck, unfortunately because it\'s a
cosmetic disfigurement more than life-threatening most of the time.
Thank goodness. And people that get them will get another one. So they
always say, I love you but I hope I never have to see you again, and I
say, well, chances are you\'ll be seeing me again so don\'t get
disappointed. And that\'s the problem with skin cancer: once you start
in that cycle of getting skin cancer, you tend to get more.

Different types of skin cancer, basal cell. This is important. I know
we\'re focusing I think on nodular basal cells, and I\'m going to go
into this later, but there are different subtypes of basal cells. They
behave differently. They look differently. I could see 10 to 15 basal
cells in a day and 10 to 15 of them look different from each other. So
there are clinically different appearances under the microscope and I\'m
going to show you some of those towards the end.

The most common is the nodular basal cell, and that\'s the easiest to
treat.

This is just an example of a pearly telangiectatic plaque, a common
location. They can be pigmented. It means nothing.

Superficial or multicentric basal cell carcinomas are these kind of
scaly red plaques that people get more often on the body than on the
face as opposed to the other types of basal cell, but tend to be very
subtle in their extension subclinically. Because they\'re superficial,
the epidermis doesn\'t show much change until it gets big enough to make
a change and you don\'t see the clinical extensions a lot of times.

Morpheaform. It\'s hard to see in this light perhaps, but it looks like
a scar. It looks like white plaque. So here we have four different basal
cells already that look different, and many more can look much different
than that.

Usually it\'s a slow course. People say, how long do you think I\'ve had
it? It\'s big guesswork. I\'ve seen basal cells that go very quickly and
a lot that have been there for 10 years or treated 8 years ago and are
still there and they show up with a recurrence.

They can get huge.

Under the microscope, I mentioned before, they have different pathologic
characteristics, but the common characteristics are they stain a dark
purple. They\'re peripheral palisading, which means that the cells at
the edges are lined up in a row, kind of, and there\'s retraction.
There\'s space between the outer layer of the cells and the surrounding
stroma or the dermis or the fat or it whatever happens to be.

The last picture was not just meant for shock value but it\'s meant to
show you that we talk lightly of basal cell carcinoma, but you really
wouldn\'t want one. You don\'t want it on your face and they can get
bad. And if you leave them alone, they can be destructive. We call then
rodent ulcers. They never stop chewing. They\'re a cancer. They just
chew away, so you want to get rid of them. Sometimes you get unlucky and
sometimes they follow nerves or they go into bone or other things.

This brings us to the tip of the iceberg theory where what you see is
not always what you get, and that is the basis for all treatment
modalities. So my standard line is, how do you know how much to treat? A
doctor is going to tell you, here\'s what I see. I better take some
normal-looking tissue around it to make sure I get it all. That
statement means the following.

Typically there are extensions of the basal cell cancer into skin that
still looks normal, and I\'m either going to cut it out or x-ray it or
scrape it or do whatever to it with some normal skin around it because I
don\'t know where that normal skin starts and where the abnormal skins
ends or anything. So I better take some extra with me. If there were no
extensions, it would be very simple. We\'d just take what we could see
and that would be all you\'d have to do, but we know that\'s not true.
So we take extra skin.

How much? No one knows. It depends on the location. You don\'t want to
take too much. You don\'t want to take not enough or you can error and
take too much on one side of it and not enough on the other side of it.
So you have all the different combinations.

Then we typically send it to a lab and the lab will look at a small
fraction of the edges, and we\'ll go into that. So again, guesswork.

And because of the guesswork, you have recurrence rates. There are a
million basal cells a year. We have lots of numbers on recurrence rates.
So not all studies are good and there are a lot of bad studies, but we
do have lots of numbers. In a clinical practice, I can tell you the
numbers are pretty accurate for what you see in practice.

We can skip this. You can scrape and burn something. That relies on the
characteristic that basal cells that are nodular tend to be softer and
easily scraped away from the skin if they\'ve never been treated before.
It\'s quick and easy. And that\'s just a clinical example.

Freezing is another well-known therapy.

Again, how far, how wide, et cetera are all the unknowns.

Radiation therapy we know about. I\'m personally against radiation
therapy for most cancers because I see what happens to people who have
radiation and you get long-term changes in your skin that end up causing
cancer, and whenever the radiation people tell you it\'s better, I still
haven\'t seen it to be better yet. So I think of it as the last effort
for certain tumors that can\'t be cleared for whatever reason and late
in the life of somebody because it\'s going to cause problems later in
their life.

Again, that\'s chronic radiation treatment now with a cancer in the
middle of the radiation that\'s already been radiated, and now it\'s a
more aggressive type of tumor. So in the center of that
radiation-changed skin is a more aggressive skin cancer, and he has skin
that doesn\'t heal as well.

Again, where\'s your portal? How much do you radiate?

Lasers can be used for skin cancer, and I believe we\'re talking about
photodynamic therapy some. You can use laser for photodynamic therapy or
‑‑ you may have heard this ‑‑ you can use non-laser light sources for
photodynamic therapy. I don\'t believe there\'s a big difference in cure
rates between the two. So non-laser light sources may be easier
financially, but the clearance rates in the studies that I\'m aware of
run about 75 percent in the studies on the ones they\'ve chosen to
treat, which is not as good as what we can do. That may be different.

But also a point to note on this is that clinical recurrence needs to be
addressed with histologic recurrence. In at least one study I\'m aware
of, 11 percent of the patients or 13 percent of the patients were clear
clinically ‑‑ excuse me. 11 percent had recurrence clinically, but 25
percent had recurrence when they looked at it histologically. So you\'ve
got to evaluate studies clinically and histologically. That\'s one point
that I will make.

Surgical excision. Again, we can say, well, let\'s guess. We\'ll just
take a bunch of skin, 2 to 5 or 3 millimeters, or whatever we\'re going
to do. Now, on the body you may take a little more and get away with it.
That\'s great. Quick and easy. 15 minutes they\'re home and that\'s
usually fine.

On the face you may not have 5 millimeters to take or you may not know
which direction to take 5 millimeters if it\'s on the end of your nose
or whatever. So then you have to make judgment calls, do I skimp here,
do I take more there, or whatever. Every time you take a millimeter one
way or the other, you\'re changing the wound. You\'re changing the
characteristic of the healing. You\'re changing what kind of repair you
need to do or not do. So, again, guesswork. But you can get good cure
rates with standard surgery.

I do this, Mohs micrographic surgery. The more I do it, the more I
believe in it, and the reason is you never know what you\'re going to
get. That\'s why there\'s this tip of this iceberg theory. Mohs
micrographic surgery, named after Dr. Fred Mohs, uses a microscope to
generate a map to tell where the skin cancer cells extend to. So instead
of guessing at margins, I\'ll typically take a millimeter or 2 beyond
what I see, usually the thickness of my pen that I mark the circle with,
cut that out. Instead of sending that to a lab, the patient goes to the
waiting room. We take the specimen in the office and we examine it and
process it in a unique way, which I\'ll show you, which looks at 100
percent of the edges of the surgical specimen all the way around and
underneath. If there is any tumor at the edge, we\'ll be able to see it
and I can tell exactly or pretty well exactly where that tumor is,
whether I need to go deeper or not, et cetera. I mark that on a map. I
bring the patient back in the room, and then we go back to where we need
to. I don\'t know how much to take, so I just take a little bit,
usually, depending on the area, 1 to 2 millimeters, maybe more if
there\'s plenty of skin there. Then I do a little bit only where we need
to, and then they get a band aid and go back out to the waiting room. It
takes another 35 minutes, and then we check that. If I see anything at
the edges of that piece, that means I haven\'t quite gotten around it
yet. So if there\'s a little extension and I\'ve chopped part of it and
I haven\'t got around it, I\'ll just keep going until I get around it.

Skin cancers are continuous in their growth pattern. They may extend out
like amoebas, and cancers are like the rest of us. They tend to choose
the paths of least resistance. So they\'ll latch onto a blood vessel or
a septia in the fat or a nerve and travel along a plane that\'s easy to
get to. But then tend to be contiguous. They tend to be one solid mass
in different shapes.

Historically Mohs surgery was mostly delegated to recurrent tumors and
tumors that were large or had a high likelihood of recurrence with
standard excisions. I said we have lots of numbers. We\'ll go into some
of those. But Mohs surgery is now used for most skin cancers on the
face, it seems like, where you want to preserve tissue. You don\'t want
to take too much. So we don\'t take any more than we need to. We don\'t
want to take too little and have it continue to grow. You don\'t want to
do a flap or graft over top of what you\'ve just cut out and hide
something from recurring, but flaps and grafts necessarily look better
on the face where you\'re moving tissue around to fix something up. So
you\'d like it to be clear before you move tissue around to fix up the
wound from a skin cancer.

In all the studies, you\'ll see there\'s nothing that is as good as Mohs
micrographic surgery, and the studies will range from about 94 to
99.something percent. The reason is, again, we take the guesswork out of
the surgery. We do have errors. We do make mistakes. The processing
could be wrong. The doctor has to make judgment calls sometimes. Is this
a hair follicle, is this a nerve, is this a muscle sheath, is this
whatever? And is this fascia or is this a tumor?

Treatments before will cause scar tissue. Scar tissue causes breaks in
that contiguous mass. So now you have to try to get all the scar tissue
out, or else you may miss little pockets of tumor that are no longer
contiguous that are growing in separate areas.

So it\'s not 100 percent, but I can tell you it\'s 99 percent. In my
practice, it\'s at least 99 percent. That\'s all anecdotal, but if you
do 10,000 cases, you\'ll see how many recurrences you get a year, and
you\'ll get an idea, and it\'s very rare if we get a recurrence.

So it\'s become a kind of standard of care where the tumor is in a
critical location, eyelids, lips, ears, and nose; the tumor is
recurrent, it\'s been treated before; and the tumor has ill-defined
margins. So you wouldn\'t even know where to start your guesswork of
where to cut out.

Not all basal cells are created equal. I\'ll show you some slides. Under
the microscope, basal cell cancers have different morphologies, just
like they do on the surface of the skin, and they have different
behavioral characteristics. Some tend to spread out more subtly. Some
tend to spread out deeper. Some are more aggressive than others. So a
soft nodular basal cell would be your least aggressive and then they go
up from there.

If I\'m going too fast, slow me down. I want to have time for questions.

You can do lots of tumors. We did a dermatofibrosarcoma protuberans
today. That was already treated twice with standard excision.

Now, these are some numbers and I have some more for you. If you do a
standard excision for nodular basal cells, you can get 90 or 92 percent
recurrence. Most of the studies with Mohs are the mostly high-risk ones
which you know are high recurrence, and we\'re still getting 96 to 99
percent. In other words, we know that the ones on the nose, eyelid,
lips, and ears tend to recur more often. We know that ones that have
been treated before tend to recur more often, et cetera.

This is just an example of breadloafing in a pathology lab, how you can
miss tumor. If you slice one and you go and slice two and slice three
and put them on a slide, you\'ll miss that in section B. There was a
tumor extension to the margin. If you examine 100 percent of the edges,
you won\'t miss that.

The patient on the left is the clinical lesion. The picture on the right
is the extent of the actual skin cancer. So again, you can\'t guess, and
it just comes up every day, day after day.

This is Mohs surgery. There is a study by Dr. Zitelli, a Mohs surgeon
who compared costs of Mohs micrographic, and it\'s a cost effective
method. If you just freeze it or burn it or scrape it, it\'s cheaper in
the short term. It may not be cheaper in the long term, but there you
can get an idea of what things cost.

This is how the tissue works. You see the tumor. You scrape away the
visible part. You cut out the visible part and a millimeter or 2 around
it. You make hash marks so you can identify location. You cut that out.
It\'s then mapped. That picture is what you cut out, so there\'s the
picture of the specimen on the patient, just for diagrammatic purposes.
There is the map you\'ve made corresponding to the tissue. You mark the
edges with inks.

DR. STERN: Excuse me. In the interest of time, could you concentrate in
the next 5 minutes on issues related to the treatment of nodular basal
cell carcinoma as a primary nonrecurrent tumor and not in terms of
technique or particular procedures? We\'re really talking about how to
treat nodular basal cells that are primary and not recurrent.

DR. ROTTER: Well, these are primary lesions, by the way.

This is what I was saying. If you\'re going to repair someone, you
better make sure they\'re clear.

Now, this study looked at all studies for a 40-year period of skin
cancer. There are very few studies that give long-term follow-up, more
than 2 years, more than 3 years. But surgical excision alone, 5,500
patients, the ones they chose to treat, had a 2.8 percent recurrence
rate. Curettage and electrodesiccation, the numbers are a little
strange, you\'ll see later. But they are 4.7 percent; irradiation 5.3;
cryotherapy, 3.7; and Mohs, 1.4. So that\'s primary basal cells. That
means they\'ve never been treated before. There are all different
comers, but if you lump them all together ‑‑ in other words, some are on
the face, some are on the body, some are on the ear.

Primary tumors. And now you look at greater than 5-year recurrence
rates, the studies that are there, 10 percent for surgical excision; 7
percent for curettage and electrodesiccation; radiation, 8.7;
cryotherapy, 7.5; Mohs surgery, 1 percent. So these are more true
numbers and you\'ll see that recurrences happen about two-thirds of the
time in the first 2 or 3 years, but 20 percent of the time they recur
after 5 years.

This is just showing you at 5 years, 20 percent more recurrences by
definition than after 3 years. And then the same thing. It continues to
go the longer you go out, so you want to look at things that have
long-term.

This was a nodular basal cell. It can go deep. You\'ll see that\'s in
the fat around a blood vessel, on a hair follicle.

Mixed types. You\'ll do a biopsy on the top. You\'ll end up with
squamous cell and basal cell mixed on the bottom.

Infiltrative basal cell.

Mixed. On the left, you can biopsy that. On part of the lesion, you\'ll
see a nodular basal cell on the right. You get a sclerosing basal cell.
So there are lots of variables. You don\'t know what you\'re going to
get to.

It\'s hard to compare one or the other. But about 10 percent for
straight surgery, about 1 percent or so for Mohs surgery for primary
lesions.

DR. STERN: Are there any questions for the speaker with respect to the
outcomes and treatments of nodular primary basal cell carcinoma?

DR. DRAKE: Could we go back to that 5-year slide?

DR. ROTTER: 2.8 percent I think was the number for surgery excision,
about 5 to 7 for other things.

DR. STERN: From the sponsor, yes.

DR. BRAATHEN: Lasse Braathen. I\'m from Bern, originally a Norwegian.
But I am the chair at the university department in Bern.

My question is, are these multi-center studies or single-center?

DR. ROTTER: This is a cumulative of 40 years of studies that were
presented that had treatment modalities, one or the other. It\'s 40
years of surgical excision studies, 40 years of C&E studies, 40 years of
radiation studies, and then ones that had follow-up of at least 2 years
were included.

DR. BRAATHEN: Retrospective compiled for many studies.

DR. ROTTER: Retrospective compiled, correct.

DR. STERN: Dr. Ten Have.

DR. TEN HAVE: Just a quick question on the next slide. I\'m just curious
about why the denominator for Mohs is so much smaller for less than 5
years and more than the next slide where it\'s 5,000.

DR. ROTTER: Right. These are long-term studies, so studies that had
patients in them for under 5 years were the 367 patients that had Mohs.
Follow-up for over 5 years, there were 5,600, whatever it was.

DR. TEN HAVE: So there have been a lot more long-term studies on Mohs
than short-term studies.

DR. ROTTER: Correct.

DR. WILKIN: I would just point out that in FDA\'s briefing document that
went out in advance to the committee, there is a study. I think it\'s
the very last section. It\'s titled Long-term Recurrence Rates in
Previously Untreated Primary Basal Cell Carcinoma: Implications for
Patient Follow-up. The first author is Dan Rowe. I think that\'s the
source of the data, and it describes the methods.

DR. ROTTER: Yes, that\'s the source. Correct.

DR. STERN: And I think earlier in the morning I sort of updated that
with Jean Lee\'s review of a subsequent review. I think all of these
data are reasonably consistent with many of the caveats we\'ve talked
about.

I\'d like to thank you very much for your presentation. Okay, one last
question from the sponsor.

DR. CLEMENTI: My name is William Clementi.

Could you speak to the issue of restorative surgery that may be required
after you perform your procedure?

DR. STERN: We\'re not here to compare costs in this way, and I just
don\'t want to get into this debate, you know, is Mohs worthwhile, do
you have bigger defects, should you go to the plastic surgeon. I think
that is an extreme off-the-track that we could be here for 3 days about.
What we\'re talking about is data that is directly related to basically
judging and putting into perspective the efficacy of the sponsor\'s drug
plus device and putting it in a historical context. So I just think
we\'re going to get into a long discussion that really won\'t move us
forward.

DR. CLEMENTI: I don\'t think I used the word \"cost.\" I think I was
getting at ‑‑

DR. STERN: No, no. I said I don\'t want to go there.

DR. CLEMENTI: I\'m not going there.

DR. ROTTER: Do you want me to answer? Okay. I\'ll make a comment on
reconstruction after Mohs surgery. Basically you have the choices of
anything. If they\'re small enough and we don\'t take much, if it\'s a
small lesion, you can keep it small. Sometimes you can let it heal on
its own. If it\'s more than that, then you have to repair it side to
side, in a sense. If you can\'t repair it side to side, then you have to
borrow tissue which is either a flap. If you can\'t repair it with a
flap, then you do a graft and you move tissue from one location totally
separate and put it on. All that is done the same day, and you don\'t
know until you get there what you\'re going to do to the patient, but
it\'s all part of the procedure.

Thank you very much.

DR. STERN: Just for clarification, you do let some things heal by
secondary intention.

DR. ROTTER: That was the first thing. If it\'s small enough, we let it
heal with second intention. If not, we go to the primary closure and
move along.

DR. STERN: Does the company want the 10 minutes now to, I guess, respond
to some questions or make some additional statements?

DR. CLEMENTI: William Clementi again. Thanks for having the 10 minutes.

We think it\'s important to clarify a few points that were made this
morning with respect to meeting minutes that were exchanged between the
division and us and with respect to some of the methods that were used
with cryotherapy and a few other computational methods that we had
performed that you didn\'t get a chance to see. So I hope we clarify a
few misunderstandings.

DR. HESTDAL: Just to go back to my last slide this morning, what we are
doing is to think that the treatment with MAL-PDT is for the indication
of nodular and superficial BCC where surgery is not desirable. In regard
to that, I think like Dr. Wilkin said, there may have been some
misunderstandings in the interpretation of the different minutes. Maybe
we could have the next slide please.

In regard to the endpoints of 307 and 308, the difference between having
clinical evaluation with histological verification or it was going to be
dependent on both clinical and histological, this was the FDA minutes
that we received on the protocol in regard to discussion of the
protocol. It says ‑‑ I am stating from the minutes ‑‑ it\'s clinical
evaluation with histological verification at an appropriate time after
last treatment. And we made the interpretation that you did a clinical
evaluation at the time, and then if it was incomplete, you excised and
then you verified your clinical response.

The next part is in regard to the number of patients for recurrence
studies. At the meeting in June 2000, a request for follow-up data on
250 BCC patients. In the minutes, there is actually no specification
that those were only nodular BCC lesions that was given. So what we have
here is that we have focused on the number of high-risk and low-risk BCC
patients that we had for follow-up. And in regard to high-risk ‑‑ we
have 112 patients in the low-risk group, and 196 patients, and that adds
up 308 patients in total for recurrence for 2 years follow-up. So I just
want to clarify that.

It\'s maybe also just a small point in regard to the biostatistics
person in regard to ITT and PP. The 303 protocol and the 304 protocol
were submitted to the agency, and we got feedback from the agency on
that protocol. For efficacy analysis, the division recommended using the
ITT population to establish superiority and per-protocol population to
establish non-inferiority.

DR. STERN: Could we go back to your first slide? I guess I\'m very
confused here because most of the data that you\'ve presented, or a
large proportion of it, are in fact people who ended up having surgical
excisions. So how did you get through an ethics committee when you\'re
trying to treat lesions that surgery is not desirable and yet part of
the protocol is ultimately taking the treated area and surgically
excising it?

We always want the data to come from the population for which the
indication is looked for. If that were the indication and then you told
me or my IRB, well, we\'re looking for these patients, but ultimately a
lot of them are going to end up getting excisions, I don\'t think I\'d
even get to come to the meeting about the approval. I\'d be interested
for Ms. Knudson\'s ‑‑

MS. KNUDSON: I think you\'re absolutely correct. They\'re either not
surgically possible patients or they are.

DR. STERN: Could you clarify that for me then?

DR. HESTDAL: I can clarify a little bit how the thinking about that is.
We have done low-risk nodular BCC and superficial BCC, and we see that
in the case of surgery, the sustained response rate is lower. So we
think that if the patient wants to have or the doctor thinks that
cosmesis, for example, is one feature that is important for the patient
and the patient should have this option to not have surgery, that\'s one
point.

The other thing is that we think we have provided evidence today that
shows that we are similar to cryotherapy. So you use cryotherapy in a
lot of your BCC treatments. We heard also the other speaker here say
that that was the case.

DR. STERN: So perhaps this is semantics. Then do you mean where surgery
is not desired as opposed to desirable?

DR. HESTDAL: Yes.

DR. STERN: Okay. That\'s a very different thing in terms of who it might
be used in.

DR. BRAATHEN: We have in our department several years of experience with
this treatment, and there are a number of patients who because they
don\'t want scars on the face and so on, and because you can use this
treatment practically in an unlimited number of times and you still have
the other options. So you keep open all other options, and if you heal
them with the PDT in the beginning without any scars, the patients are
very happy. So that\'s the rationale of all this thinking. And in the
clinical setting, I think we have to agree that the patients more and
more are looking at the cosmesis.

DR. STERN: I\'m sorry. The sponsor hasn\'t used its 10 minutes. Did it
have additional things it wanted to bring forward?

DR. HESTDAL: That\'s right. So then we also have in regard to the skin
sensitization ‑‑ maybe Lasso can come back.

DR. BRAATHEN: My name is Lasse Braathen. I said that previously. I\'m
educated in Germany and in Norway. I have three specialties,
dermatologist, allergology, and clinical immunology and angiology, and I
also have a master in health administration.

The FDA is curious about the unusually high rate of sensitization. If
you look at what is around in products over the counter, you will see
that a lot of these products contain parabens. Benzoyl peroxide, for
instance, is an over-the-counter drug here in the States I think.
Benzalkonium chloride. And if you submit these substances or these
over-the-counter preparations to the kind of procedure which has been
done in this sort of guinea pig maximization test, then I think you
would get sensitization in most of them.

The second issue is what is the problem of sensitization. I have treated
probably, my own patients, about 300 or 400 treatments, and a lot of
them are repeaters. They come regularly for treatment because it pops up
new and it\'s mainly actinic keratosis but also occasionally basal cell
carcinomas and Bowen\'s. In our department, we have treated more than
2,000. We have not seen one single case where we suspected a contact
sensitization.

Now, a phototoxic reaction does not give papules, does not give the
vesicles unless you burn the patient. A photoallergic reaction or an
allergic reaction is defined as T cells which are specific for the
particular antigen and it spreads. We all know that if you test it, it
spreads outside. I\'ve never seen any cases where I even got the idea
that there\'s an allergy behind it. All have typical phototoxic
reactions and it\'s like sunburns. That\'s my clinical experience.

Now, the second thought is, does it really matter. We use drugs which
induce immune reactions. We use diphencyprone which is an obligate
contact dermatitis antigen for treatment of alopecia areata. We induce
on purpose a contact allergic reaction in order to treat the patient.

Secondly, a new drug which is now coming is imiquimod which acts over
the receptor 7 and induces an immune reaction, a very strong immune
reaction. You have to treat the patients for 3 months, and the patient
is going around with heavy skin inflammation for all that time and we
are happy when the lesions then clear at the end.

So to me I don\'t think it\'s really an issue. If there is some contact
dermatitis in addition to the free oxygen radicals ‑‑ it\'s even also
described apoptosis in the lesions ‑‑ then I think I would be happy if
there is an additional thing going with the rash which is helping us to
cure the patient.

Earlier today, the question was how far down in the skin does the red
light penetrate. It\'s about 5 millimeters.

Another question was the time for the freezing and we have the data now.
It\'s 35 plus/minus 12 seconds. The range was 20 to 90 seconds and the
median 40 seconds. I guess that the reason for this, they\'re all
experienced clinicians, and you know, as well as I do, that everybody
does the freezing in his own way.

I believed, when I was younger and until I saw these studies, freezing
studies in actinic keratosis, cryotherapy, that cryotherapy was 100
percent until we saw the results of the prospective study. We also all
know we have to admit that. I\'m certain that Professor Stern also will
admit that. I would never allow a publication out of my department that
showed that my basal cell carcinoma treatment results were much less
good than what was the average. I would then not publish. So what we see
as published data are mostly from people who are very proud of their
results and with right because the data we saw here today of recurrence
rates with different methods are superb, but there is no incentive to
produce or publish bad results. And we know it.

So, in effect, in our department we use this as a routine method for
actinic keratosis and for selective cases of basal cell carcinomas, and
that is these cases where we try because of the cosmesis. It may be on
the eyelid here and also here where we then see this is going to be a
major surgical thing and the result is very unsure. So let\'s try
something else first which we know has a very good cosmetic result.

Thank you very much for your attention.

DR. MURRELL: There was one more answer to your lower leg question.
Because in the high-risk studies, the patient\'s locations were coded by
extremity, face, or scalp or trunk, I can only summarize for the
extremities, but there didn\'t seem in our studies that there were many
of these large lesions on the upper limb. They were mostly the lower
limb, but I\'d have to go back, get the CRFs out to tell you
specifically below the knee.

But there were 30 extremity lesions in the 310 study and 91 percent
complete response rate at 3 months when the biopsies were taken. 18 of
those were characterized as superficial lesions, and 17 out of 18 were
complete responders, 94 percent, and at 2 years, 2 out of those 17 had
recurred, with a 12 percent recurrence rate.

In the 205 study, there were 6 superficial extremity lesions. I don\'t
have the total number extremity lesions, but 5 out of 6 had responded
completely at 3 months and at 2 years none of those admittedly small
numbers, 5 had recurred.

Thank you.

DR. STERN: I think we\'re once more open for committee discussion, and I
think it was Dr. Ringel\'s turn for her questions 2 through n.

(Laughter.)

DR. RINGEL: Hopefully we won\'t get to n.

One thing that I think would help me is actually to see this kind of in
progress. We\'re talking about if there\'s an allergic reaction, if
there\'s a phototoxic reaction. Do you have any pictures of what this
looks like the day after, a week after? Do we have any clinical pictures
with us so we could actually lay our eyes on this thing as it goes
through?

DR. HESTDAL: Sorry. We don\'t have them with us.

DR. RINGEL: Another issue was on page 52, figure 9, you have a nice
picture of histology versus the penetration of MAL into the basal cell
carcinoma. One way to address the penetration ‑‑ we don\'t really care
so much ‑‑ well, of course, we do ‑‑ how far it goes into the skin. I
think people are concerned does it go into the skin enough, and more
important, does it go into the basal cell carcinoma enough. Have you
tried to do any studies which compare lesion depth to percent
penetration? In other words, will it penetrate a 3 millimeter nodular
basal cell carcinoma, a 5 millimeter, a 7 millimeter, that sort of
thing?

DR. HESTDAL: Did you ask if we have looked for penetration?

DR. RINGEL: In other words, if you have a very deep basal cell
carcinoma, what\'s the maximum this will penetrate? Will I be able to
treat a 7 millimeter deep basal cell carcinoma or a 10 millimeter deep
basal cell carcinoma? Do you have any data that compares depth of
penetration of MAL to the lesion depth?

DR. HESTDAL: We have looked at the data in 307 and 308 in regard to the
depth before including the patient and then the results. I think one of
the studies showed that there was no ‑‑ I think we have the lesions up
to 5 millimeters in depth and there was no difference in response in the
different superficial or nodular.

The other thing is that we have looked at the penetration depth in
regard to measuring photoactive porphyrins. In this study no nodular
lesion was larger than 2 millimeters in depth, but we achieved this 98
percent relative penetration depth. So both clinically, as well as with
the fluorescence measurement, I think we have data that indicate that
you can treat pretty deep lesions.

DR. BRAATHEN: Maybe I could add. There is guidelines for photodynamic
therapy which is given by the British Association of Dermatologists. It
is now published in the British Journal of Dermatology. And they
conclude that they recommend that lesions up to 3 millimeters can be
very efficiently treated with PDT.

There is a way to solve that problem. If you have a lesion which is
thicker, you debulk it and you stop the bleeding and then you apply the
cream.

DR. RINGEL: And the last question I have is back to the data from one
cycle of treatment, two sessions, but one cycle. I have many patients
where I do the biopsies and they don\'t come back because, as far as
they\'re concerned, it looks so much better. It\'s very hard to get them
back to the office. It\'s going to be even harder to get people back to
the office who have two treatments of this 3 months later. There are
going to be a lot of people who are going to get lost to follow-up.

So I was wondering, once again, I know the FDA didn\'t have the means to
have any data on this, but perhaps in some of your earlier studies, do
you have any data of what kind of cure rates you got after one cycle of
MAL-PDT?

DR. MORRIS: I don\'t think that the studies have been generally designed
to look at one or two treatments.

DR. RINGEL: It felt as if you must have had a reason to do two cycles
rather than one cycle because obviously you didn\'t feel that there was
a sufficient cure rate for one.

DR. MORRIS: Yes.

DR. RINGEL: So I was wondering what the data was ‑‑

DR. MORRIS: We realized from the phase II data that about a third of the
patients, roughly, had to come back for a second treatment, and that has
been shown again in the phase III studies. Roughly, but I don\'t have
exact figures here.

DR. STERN: I think Dr. Katz was next.

DR. KATZ: Are you finished with your questions, Doctor?

DR. RINGEL: Yes, I am.

DR. KATZ: On this DVD, was that an actinic keratosis treated or a basal
cell carcinoma? We were given this DVD. We were given a demonstration.
It was very well depicted.

I have some comments because I\'m a practicing dermatologist. I see
maybe an average of 400 basal cell and squamous carcinomas a year and
actinic keratoses at every hour. To think of having a patient come and
wait 3 hours and put medicine on and then treat it with this machine,
when I can spray ‑‑ and yes, I always tell people, as artful as we are,
we do get an occasional white spot. But it\'s astounding to me that that
would be done.

The other question I have, amongst others, Dr. Hansson, that first slide
you showed of the patient who had a recurrence after Mohs, how many
patients have you treated with this therapy with Mohs recurrence like
that?

DR. HANSSON: I don\'t think it\'s correct to call this particular
patient a recurrence after Mohs surgery. This was a patient with a very
large lesion, as you saw, on the nose where they started Mohs surgery,
but because of excessive bleeding and problems with anesthesia, they
couldn\'t finalize it.

DR. KATZ: I see.

DR. HANSSON: And as an alternative, in this particular patient, the
primary option was not possible, and since we, at the same time, were
doing this study in Australia on difficult-to-treat or high-risk basal
cell carcinoma, this patient was then included in that study.

DR. KATZ: Thank you.

People alluded to patients not desirable for surgery on anticoagulants.
I think the literature is now quite adequate in the last couple of years
that patients on an anticoagulant ‑‑ one study specifically in Mohs
surgery, that was no problem and they had no problems with aspirin as
well. Those studies are in the literature. We have worried about that
for years. The standard was to call the internist, ask him to take off
the anticoagulants for a couple of days, but now we know that even
deeper surgery in the general medical literature can be done with
anticoagulants. So I think that shouldn\'t be used.

I think we should not spend too much attention on the cosmetic issue
because obviously if you have a treatment that gives a much poorer
result, you\'re going to get better cosmetic results. In other words, if
you have after 3 months a 47 percent treatment effect at 3 months rather
than a 95 percent at 5 years, obviously you\'re going to have a better
cosmetic result because you\'re not getting rid of all those other
tumors.

The other point was the big point not getting hypopigmented results. But
on page ‑‑ if I can find it. The slide on the person\'s back. What page
was that? I had it flagged. 124. I have no criticism of the photograph.
No, it\'s not 124. It\'s the person\'s back in the red book. Right,
thank you.

That picture to the right is fuzzy. I have no criticism of that, but if
one looks closely, you can see four hypopigmented areas. Obviously
that\'s no criticism of the treatment because if you treat adequately,
you\'re going to get post-inflammatory hypopigmentation no matter how
you get rid of the tumor. If it\'s extending down, you\'re destroying
dermis. So I don\'t think the cosmesis should be a major issue.

Many of these lesions are treated and a lot of time is spent taking care
of these patients where a simple surgical excision with ‑‑ I think it\'s
pertinent that the bias ‑‑ and we have Dr. Bigby here ‑‑ against
negative studies ‑‑ I agree, they\'re not published.

But we clinicians rely on some statistics, and then you figure in your
own mind how many basal cells you treat and if you try to be
self-critical and you think how many recurrent basal cells have I seen
in the last year ‑‑ now, true, many patients won\'t come back, but we
still would see recurrences that colleagues have treated. So the
recurrences that don\'t come back to see me, on the other hand, I would
see colleagues\'.

Generally speaking ‑‑ and I don\'t have any hard data ‑‑ also speaking
to colleagues in my own journal club which has been going for over 30
years ‑‑ and it\'s informal, so we\'re very self-critical. It generally
hangs in there as indicated by the literature. You get about 5 percent
recurrences.

Now, that\'s because you\'re referring patients who are not appropriate
to what we\'re doing. I don\'t do Mohs, and I don\'t do extensive
plastic surgery. So that wouldn\'t correspond to where surgery is not
desirable. Just because I can\'t do the surgery, that doesn\'t mean
it\'s not desirable. It\'s a very simple thing in this world to refer
people where it\'s most appropriate, and if we can\'t take care of it,
then Mohs.

And the general results that Dr. Rotter gave with 1 percent recurrence,
1 to 2 percent repeatedly occurs in the literature, and if I think of
the recurrences that I see relative to the people that we refer to Mohs,
it\'s in that ball park. It may not be exactly that. It might be 3
percent. We\'re talking about figures like that, and here you\'re
talking about a complete response rate of 47 percent on that other slide
that we were discussing, 2-year complete response rate of 9 percent, if
you eliminate the people not showing up, and 34 percent if they include
those as failures compared to 16 percent in the surgery group. That\'s
at 2 years.

The article referred to in the FDA document showed ‑‑ I forget the
number, but only 50 percent of the people who are going to have
recurrences show up at 2 years.

So we\'re talking about certainly a treatment that is better than
placebo, but in practice, if you offer it to a patient a treatment that
was better than placebo and they\'d have to go through all of this, wait
for 3 hours and have two treatments, come back in 3 months for another
trial of two treatments, I\'m sorry. I mean, with all due respect ‑‑ and
I do respect and appreciate our colleagues from Norway coming. With all
due respect, it\'s very insufficient. If I landed on this planet now,
instead of having 35 years of experience, and somebody showed me this
treatment with this light and then somebody else said, yes, but I could
just cut it out or even the most extensive thing we\'d go to is Mohs
surgery and you\'ve got to be around for a couple hours, I\'d say we\'ve
made an advance in 200 years. And when I say 47 percent, that\'s not
including Dr. Alosh\'s statistics which really decrease that cure rate.

DR. STERN: I\'m sorry. A representative of the sponsor wanted to make
comments.

DR. MURRELL: Just in response to the 3 hours, about how the patients
react to that. In the studies, what we normally have done is have the
patients come in for a short while to prepare the lesion and put the
cream on. At least in Australia, our patients then go off shopping,
spend the 3 hours. They don\'t wait in the hospital. They go off and do
something they want to do, and then they come back 3 hours later. So
they\'re not usually waiting in the office for that time.

DR. STERN: Jimmy.

DR. SCHMIDT: I guess I\'m really unlucky to have landed in Houston and
worked at M.D. Anderson because I really think that some of these
bleeding problems that you see with some of these patients with cancer,
as Paula can tell you, are a very serious problem. I realize the simple
patients that you might see you wouldn\'t worry too much and you
wouldn\'t even stop the anticoagulants. But we really see some absolute
horror shows two and three times a day even. I really think we need
something else. Of course, I think we have good radiotherapists too
where we get a small recurrence rate. But I don\'t know. I think that
this thing about the bleeding ‑‑ I think that there are some real
questions here, when you\'re in a situation like some of us are, that we
need some of these things.

Paula, do you have a comment on that?

MS. KNUDSON: I understand exactly what you\'re saying and I certainly
had our dermatology people reporting a lot of adverse events with a lot
of bleeding on their cancer patients. I don\'t really know anything
about radiotherapy, however.

DR. KATZ: But there is data. There are studies with Mohs with patients
on anticoagulants.

DR. BULL: I think we need to keep our discussion focused on what\'s in
the application.

DR. STERN: Exactly.

DR. BULL: That\'s a context that has not been studied.

DR. STERN: The application and the data that support it, as I
understand, are for the treatment of ‑‑ I\'m using the word \"primary,\"
that is, nonrecurrent superficial and nodular basal cell carcinoma, and
it doesn\'t get into the issue of ‑‑

DR. WILKIN: I guess this is actually for the sponsor. I thought I heard
them say today they\'re not seeking high-risk. So they would exclude. It
would maybe be rewritten in a way that it would actually say maybe
low-risk.

DR. MORRIS: Yes, that\'s correct. That\'s also the indication that we
have in the other countries where the treatment is approved where it\'s
for treatment of basal cell carcinoma where other treatments are not
suitable, and in Australia, where surgery is not appropriate.

DR. STERN: Well, that\'s, the way I hear it, not exactly the same thing.
To my mind, although I don\'t like the terminology \"low-risk\" because
one can think of low-risk in a whole variety of ways ‑‑ what are the
chances of recurrence, how large is the cosmetic defect likely to be
from it. There are a whole variety of parameters that go into the risk
of a tumor in an individual beyond their underlying health state and
anticoagulation.

But what you\'ve said, as I understand it, you\'re basically approved
for tumors where, shall we say, the more conventional therapies are
generally not thought to be appropriate. And what I understand is in the
studies that we\'ve seen today, the subset being treated are exactly the
patients for whom other modalities are appropriate. So once more, I
bring up, at least in my poor mind, this disconnect between the data we
have and what the relevant characteristics of the patients studied are
versus the fogginess in my mind about what indication is really being
sought at the end of the day.

DR. MORRIS: We did face, in a way, a dilemma when we were designing the
clinical studies because we wanted to have excision as the endpoint
since that is what we agreed on as an appropriate endpoint to determine
the outcome. We also wanted to compare to conventional therapies. So we
needed to do studies on patients where surgery was appropriate, but on
the other hand, we have also included these other studies where surgery
is not so appropriate in some of these patients as supportive evidence.

DR. STERN: Do you wish to make a final comment?

DR. LUKE: No.

DR. RAIMER: Well, my comments were a little bit similar to Dr. Stern\'s.
The trouble I\'m having is it seems that for a small nodular basal cell
carcinoma, that this treatment is clearly inferior. But as a clinician,
I would really like to have it for large superficial basal cells on the
legs which are very difficult to treat. You have to excise and graft.
There\'s a lot of morbidity. For the patient we saw on page 125, the
large fairly superficial-looking lesion on the nose, it seemed to work
well. I mean, I would like to have it for that sort of patient. That\'s
not really a low-risk patient.

Are we allowed to consider like in European countries the indication for
lesions that are not appropriate for treatment ‑‑

DR. BULL: I think when we get to the questions, because I think you also
have to address the sufficiency of the data in the application. I would
not be swayed by the fact that a few pictures were included in the
submission and be persuaded by that. I think you also have to look at
the numbers, the quality of the data, what the comparators were, and to
make a decision or a recommendation that\'s based on data that you can
deliberate in a way that provides sufficient context for a
recommendation on a particular subset of patients. So I think that that
may be something that you can look into as you move into the questions.
Whether or not there\'s sufficient data in this particular submission to
substantiate that as a claim I think is entirely another issue.

DR. STERN: Dr. Bigby and then Dr. Tan.

DR. BIGBY: This is just a question about the procedure. Is the amount of
time that the light is shown determined by sort of metering the
milliwatts per centimeter squared at the surface of the patient at the
time of treatment and then you calculate how long the light should stay
on?

DR. MORRIS: Yes. The lamp calculates how long the time should be to
deliver the dose of 75 Joules per square centimeter, which is the total
dose to be delivered.

DR. BIGBY: Based on some measurement taken at the surface?

DR. MORRIS: Yes, because you set the size of the diameter of the light
field and then you have to calibrate and see the intensity of light that
you have at the skin surface using that distance, and then the lamp
automatically calculates the time and it will turn itself off.

DR. BIGBY: But is that just based on the diameter and the distance, or
you actually meter the surface?

DR. MORRIS: We measure it with a probe.

DR. TAN: I just want a clearer mind on the assessment of response rate.
For the two pivotal trials, at the end of the 3 months, you have the
complete responders. For those patients that will remain to be clear at
6 months. Right? Is that true or not so? In other words, those patients
who are complete responders don\'t have a recurrence within 3 months,
the follow-up of 3 months.

DR. PARISER: The number 6 months was 6 months from enrollment.

DR. TAN: So one patient has responded. At the end of 3 months, he\'s a
complete response. In another 3 months ‑‑ so that\'s the end of the ‑‑
that\'s at 6 months. Right? And at 6 months, when you look at this
patient again, does this patient have recurrent disease or not?

DR. PARISER: No. Every patient is examined 3 months after the last cycle
of their treatment.

DR. STERN: Dr. Drake?

DR. DRAKE: I just want to compliment the company for tackling this very
difficult area and this very difficult subject to study. I can tell you,
we have precious little data that\'s adequate in my opinion in any area
of treating skin cancer. Maybe it\'s because I\'m biased because I\'ve
been at tertiary referral centers my whole career, but I tend to see
what other people think they\'ve gotten rid of and it tends to show up
at our place in many instances.

I don\'t think we have good tracking. There\'s no tumor registry. I
chaired an NIH panel on outcomes for non-melanoma skin cancer, and in
fact there are no registries for non-melanoma skin cancer. We don\'t
have any way of really tracking any of this in a very sufficient manner.
I think the data is weak in general on what really happens to skin
cancer.

So I want to thank the company and the FDA both for trying to make some
sense out of a very difficult subject. So I wanted to say that as a
header because I think the panel is trying to hang numbers on things and
rely on these numbers, and in fact, these numbers maybe are not the
best. But guess what. They\'re at least an addition to what we know,
which is in some respects not adequate.

Now, I tend to agree with some of my other colleagues. I think this is a
niche product. I think this potentially has a role for a subset of
patients that we need something for. I agree with the big superficials
on the lower legs on diabetics. I agree with people who are on
anticoagulants because I think these are problem patients.

I also think there are some patients who just, due to a variety of
reasons, really don\'t want cold steel surgery, and if you have
something less invasive and less problematic to offer them, they might
be very grateful for that opportunity. I\'ve seen C&Ds done by doctors
who are superb and get superb results. I\'ve also seen C&Ds done by
people who don\'t get any kind of decent results and you have really
nasty recurrences. This in fact might be helpful to those people. If
they don\'t know how to do a C&D, perhaps using light and a photoactive
drug, a PDT therapy, might actually help them get the tumor that they
can\'t seem to get with a C&D.

So I\'m going to speak for this. If we approve it, I certainly don\'t
think that there ought to be broad claims or broad indications or broad
anything. I think it\'s a niche drug, and I\'ve seen this committee
approve niche products before for a subset of patients where something
may be needed and this is something new that\'s come along that might be
useful in that arena.

DR. STERN: I think we\'re about ready to move on to the questions after
Dr. King, and I\'ll perhaps ask one final question.

DR. KING: I have to be agreeable with what Dr. Raimer said and Dr. Drake
said, that there\'s a great deal of empathy, having practiced both now
in the VA and the tertiary care and now in a private practice type
setting, that there are patients who, for a lot of reasons, need a niche
product.

My other point is that, on the other hand, once you open Pandora\'s box
or, in the South, a can of worms, once you put something out there
that\'s FDA-approved, how are you going to ensure that
non-dermatologists are going to do skin biopsies or have the ability to
follow it up? It\'s been my experience with laser, which has an enormous
complication rate in Nashville because everybody has got something where
if you shine the light on, you\'re going to open up the pocketbook, that
people buy these things and use them without a great deal of training.
So I guess my concern is how would we write the PDR or the instructions
about who\'s to use it and how to use it and how would the insurance
agencies or Medicare view this when simply sometimes it\'s instruction
by any means.

So I\'m favorable for niche and then I\'m worried about, yes, but if you
put a gun in the hand of a 4-year-old it\'s different from a
40-year-old. So we should be very careful about how we define the issues
here: niche versus broad-based.

DR. DRAKE: Lloyd, I want to respond to that. I think you\'re right. But
we have other things out there that used in the wrong hands by the wrong
people cause lots of problems, and that hasn\'t stopped us thus far. So
I think we ought to think about how carefully ‑‑ Lloyd, you\'re exactly
right ‑‑ can we write the labeling and how cautiously can we do this so
that it\'s used appropriately. You can\'t regulate behavior all the
time, but what you can do is you can try to give people an opportunity
to understand how something is to be used and hope it helps some
patients because my bottom line here is are there patients that this
product might help. I think that\'s where my goal is. Is there a subset
of patients where this might be a useful product?

DR. KING: My back-comment is if 40 million people do something dumb and
stupid, it\'s still dumb and stupid.

(Laughter.)

DR. DRAKE: Lloyd, how many dumb and stupid things do you see done every
day with stuff that\'s already approved?

DR. KING: A lot.

DR. STERN: I would hope that we would stay on both the evidence and the
indication. I guess before we start the questions, I would like to share
another way of how I\'ve synthesized these data, and that is, what would
be informed consent for a person with a small nodular basal cell
carcinoma coming to my office who is perfectly healthy, not a niche,
basically eligible for these trials? So how would I express this on the
face relative to the other therapies available? And let me tell you how
I would have to do it, as I synthesized these data.

Well, I can send you to the Mohs surgeon. It\'s going to take a half to
a full day of your time. The chances of recurrence after that are 1 to 2
percent. Unless it\'s a big tumor, in which case you really needed it,
you\'ll have a good cosmetic result. If you have a big defect and a bad
cosmetic result, it means it was good that I sent you there. It was one
of these so-called iceberg lesions. So that\'s one possibility.

I can send you to a skilled surgical colleague, be they a dermatologist
or a plastic surgeon, and they\'ll excise it. It will take 35 minutes
and you\'ll have an excellent cosmetic result. The recurrence rate at 5
years might be as high as 5 percent, although the person I use is much
better. So since I think it\'s an appropriate lesion, it will be less,
but I\'m just joking when I say that part. So that\'s the second option.

Or you can have me, who doesn\'t remember to press the button, do it,
and I can do it in two ways. I can do it with curette and
electrodesiccation which will leave you a depressed scar. If you let me
leave a big enough one, I\'ll give you the same recurrence rates. If you
want a smaller scar, the recurrence rate will go up because it depends
on borders. Or I can do just cryosurgery and probably the same
recurrence rate, and you\'ll have a white mark, a flat, macular scar in
most cases that will be red originally, and probably a slightly higher
recurrence rate. And we can do that in the next 10 minutes, but you\'ll
have oozing and you\'ll have to take care of it for 3 or 4 weeks, but in
fact you can do anything that you could do if you had gotten a scrape
falling off your bicycle basically in terms of postoperative care.

So those are the available options.

Then I have this new option. The way I read these data is the other
option is, as opposed to the half-day, one-time, and a suture removal,
the 35 minutes, and a subsequent suture removal, I can send you for what
on average will be three visits which will require for someone to scrape
the lesion, apply it, have you return 3 hours later that day for
irradiation, then after two treatments a week apart, wait 3 months to
see if it\'s really working, to see if you need two more treatments a
week apart, each time, scrape, apply the medicine, wait 3 hours. In
addition, on the basis of my synthesis of all the available data
compared to Mohs, the chances it will come back are certainly at least
five times higher and, compared to the other modalities, are likely to
be at twice as high.

So that\'s the informed consent that I would have to give a patient in
describing using this treatment for a small nodular basal cell carcinoma
on the face. And you\'re right. I didn\'t mention any other non-approved
chemical entities for nodular basal cell and I didn\'t mention x-ray
therapy because we talked about it being a young, healthy person and
that\'s not a good idea to do.

Now, if that\'s an unbalanced review for, as I understand it, the target
audience who really cares about cosmesis, as I\'ve heard, would someone
tell me what went wrong in my describing our best information as it
stands now?

DR. PARISER: Well, I\'ll take a shot at that, and you\'re right for the
small nodular basal cell on the face. For the superficial or nodular
basal cells on the lower leg where part of your informed consent for the
C&D would be you may have a non-healing sore there for weeks, for your
excisional, part of your informed consent would be you\'re going to have
a big scar there, it may or may not be able to be closed without a
graft. It does change that a bit.

DR. STERN: How many lower-limb, below-the-knee lesions were in the
randomized, controlled studies?

DR. PARISER: That\'s another issue.

DR. STERN: I\'m talking about the evidence base and the application. We
all wish for something that would take care of our problematic cases,
but that\'s not, as I understand it, our mission here today to decide
about this product for things we wish we could do better.

DR. PARISER: Specific numbers on the superficial ‑‑

DR. KATZ: Everybody is focusing on lower-limb lesions. When this
destroys this large basal cell, doesn\'t it leave an ulcer? The lesion
is being destroyed. You mean it just heals the next week magically or
might it take 3 or 4 weeks? I cannot imagine a large basal cell, which
we would all love to have a magical treatment for, that this goes away
and epithelializes on a lower-extremity lesion.

DR. PARISER: Well, it certainly epithelializes or heals much different
from cryo or from a C&D in that area in terms of healing time.

DR. KATZ: That\'s what I would suspect. So that\'s the point. The point
is where these folks are looking for wonderful treatments for
lower-extremity lesions, like Dr. Raimer and myself included, this is
not inferior or superior to that unless you get a higher recurrence
rate. If you\'re going to get a higher recurrence rate, which we do
have, it\'s going to heal much faster with this treatment because
you\'re not treating as much of the cancer.

DR. BRAATHEN: Of course, the chairman is right in his description of
what do you tell the patients.

Now, if you have a patient with cancer, you have biopsied it and you
say, you have a basal cell carcinoma and we have to cut it out, but
there will be scars, the patient will say to you, it doesn\'t matter as
long as you remove it. If you give the patient the option, as you so
nicely described, and said, there are several treatments, there is one
treatment which gives less scars than the other ones and less
complications ‑‑ there are published studies also on cryotherapy which
show more complications ‑‑ but which gives you less scars and in case it
recurs, we can do the treatment several times, and we still have all the
other options open, that\'s what I tell my patients. And most of my
patients, if not all, jump on the PDT. They want something which gives
them less scars. I think I\'m doing my job then by giving them this
treatment.

DR. STERN: Dr. Wilkin.

DR. WILKIN: Yes. First of all, I think in Dr. Drake\'s lexicon, she
calls it \"niche,\" and we think of them as somewhat well-defined
indication groups. But however you want to call it, I think we are
interested in knowing if there is that segment of the data that might
support that. And along that line, Dr. Katz actually mentioned would we
have data for superficial BCC, recurrence data. I have to tell that the
agency was not relying heavily so much on this because we were
approaching this from the construct of first one achieves nodular and if
there\'s success in nodular, then we\'ll look at the superficial BCC
data.

But we do have a slide. It\'s by patient recurrence and perhaps the
sponsor has some way where they can break out the recurrence data for
superficial. I think that would be directly responsive to Dr. Katz, but
in the meantime, we could show our slide 18 and the additional slides.

Actually in the sponsor\'s document on page 110, table 65, they have
lesion recurrence rates at 12- and 24-month assessment. This is the
agency\'s evaluation as a patient recurrence. I think the notion was if
there are several of these superficial BCCs, a patient would come in and
get all of them treated. So we were interested in the analysis of
whether the patient would have to come back.

But these are the sponsor\'s data on page 110. This is ours. The sponsor
may want to speak to this. It\'s in the interest of what Dr. Drake was
mentioning about the niche.

DR. STERN: Would the sponsor want to comment?

DR. FUGLERUD: Yes. This shows the patient recurrence rate after 12 and
24 months, and a patient was defined as a recurrent patient if at least
1 of the lesions within the patient was recurrent. So it was categorized
as recurrent if at least 1.

The corresponding lesion recurrence rate after 24 months was 17 percent
in the MAL group compared to 20 percent in the cryotherapy group.

DR. STERN: Thank you.

DR. HESTDAL: I think we have today shown the sustained response of both
cryotherapy and MAL-PDT in the same studies. Is that what you would like
to see?

DR. WILKIN: Well, actually it\'s for the committee for their
deliberation, but I thought what you had was a way of looking at the
recurrence rate for superficial after your modality. Again, I thought it
was on page 110 in your briefing document.

DR. FUGLERUD: I think it\'s table 65 in the briefing document. It\'s on
the screen also. So it\'s the recurrence rate after 12 and 24 months,
and that\'s the recurrence rate calculated among the lesions in complete
response after treatment. So in the MAL group, it\'s 108 lesions and in
the cryotherapy group, it\'s 94 lesions, and the recurrence rate after
24 months is 17 percent in the MAL group compared to 20 percent in the
cryotherapy group.

There\'s 7 percent missing in the MAL group compared to 5 percent in the
cryotherapy group. So the recurrence is calculated without the thing
missing as recurrent.

DR. STERN: I\'m a little confused in how there are 8 missing. When you
exclude missing values, it goes from 108 evaluable lesions to 91, and
where I come from, that\'s a difference of 17. I just don\'t know how 8
and 91 get up to 108. So could you just clarify that for me?

DR. FUGLERUD: Yes, I understand the question that the missing value
column is a little ‑‑

DR. MORRIS: In the life table that we showed you this morning, we have
this data. We can find it.

DR. STERN: It\'s not really essential. It\'s just I got confused.

DR. FUGLERUD: Yes, I understand. But can you take this back again, this
table?

I agree that there is a mismatch between this 108 and this 8 missing, so
we will check this. But the calculation handled as missing is in the
second column and in the fourth column.

DR. STERN: Does anyone have an extremely pressing issue that they don\'t
believe would be covered as we go through the questions?

(No response.)

DR. STERN: Good. So why don\'t we move on to the questions, which I\'m
sure, since part of the questions are likely to elicit questions, may
help and direct us to the specific reasons that the agency has turned to
us for advice about this application.

So question 1 is: The investigator\'s manual included the following
lesion preparation instructions for use. \"Tumor fragments from most
lesions may be removed without damaging normal skin and without use of
anesthetics.\" And here the question is ‑‑ I think it should be, was
lesion preparation instruction adequate to ensure sufficient consistency
among operators?

DR. WILKIN: That seems to invite a yes or no response, and what we would
really like to hear is something more than that. We would like to
understand if more might be added to this to make it understandable and
helpful and consistent with how this was done. I think we heard, at
least I heard for the first time today, from Dr. Pariser the phrase
\"curettage and lesion debulking,\" that that was the understanding that
the investigators had. But we\'re looking for what we might craft into
labeling.

DR. STERN: I guess I\'d like to start with a couple of comments. One is
‑‑ I\'m sorry I can\'t find the page, but in the illustration of
curettage that\'s in your diagram, it didn\'t like you were instructing
individuals to basically take off what was above normal epidermal level.
In fact, the way it looked to me is the instruction was to go below
because it looked like there was supposed to be a depression, an erosion
or ulceration left afterwards.

Secondly, where I come from, when you\'re trying to put forward a
therapy, I always show my best results, and at least on page 123, the
pre-application, post-curette slide showed to me what looks like my
usual kind of first-time curetting.

Oh, I\'m sorry. We can\'t discuss with you anymore. We can only ask for
clarification.

So to me that, combined with what was pointed out, was heterogeneity in
fact both in the controlled studies ‑‑ both within the sham group that
got curettage and the treatment group, there was tremendous
center-to-center variability between centers for both. If you looked at
what you could perhaps attribute to curettage alone and you looked at
the cure rates there, in some centers a large proportion of tumors were
cured without the aid of an active MAL-PDT basically, without the MAL
part of your PDT, a sham PDT. So that to me suggested that it\'s either
patient selection variability or in fact variability among operators and
what they did or perhaps evaluators in what they took to be a
recurrence.

But certainly when you go from 0 to almost complete cure rates with
small numbers, it suggests that not everybody is either treating the
same patients, looking at them afterwards in the same way, or doing the
same thing in the control group, which suggests that even among trained
investigators, that there\'s heterogeneity in the interpretation of the
results in the investigator brochure. I think we need more direction if
it\'s going to be labeled.

DR. BULL: I just wanted to remind that given that we\'re in the question
part of the meeting, that the questions are directed to the committee.
You\'re beyond the point of clarifying. You have to basically deliberate
based on what\'s been presented and discussed.

DR. STERN: Ms. Topper just informed me in capital letters about that.

Each individual who has comments about this should make them. I think
what we\'ll do is start with the voting members of the meeting, and if
Dr. Plott has something particularly pressing, we\'d love to hear his
comments as well, but he\'s non-voting.

DR. RINGEL: In brief, I agree.

The only other comment I could make is that we also heard that the
company really didn\'t feel that they could count on MAL penetrating
more than 3 millimeters into a lesion. Therefore, they should be
curetted, rather than just superficially abraded. It sounds like a
nodular lesion that you think may be very deep really should be
curetted, if that\'s truly a concern for them, and I think it should be
standardized.

DR. TAN: Yes. I just want to add maybe you should use some kind of
range. Instead of giving a firm limit, 3 millimeters, maybe 3 to 5. I
don\'t know. That might be something worth considering.

MS. KNUDSON: As I recall, somebody said that curettage was not supposed
to be a therapeutic curettage. Would that be language that all
dermatologists would understand, that you would not be doing a
therapeutic curettage when you\'re doing this preparation?

DR. STERN: This one wouldn\'t.

DR. KING: I guess I think about this as more like curettage and
photodesiccation. Being a dermatopathologist, I\'m on the other end of
this. So what you see in, say, 10 dermatologists is 14 ways of what you
get. So I would like, if they could do that, standardize it, but as a
practical matter, I doubt if you will. Maybe perhaps you could talk
about slicing with a razor blade so that you don\'t cause pain as
opposed to taking the razor blade made into a curette and dragging it
across there. So I wish I could come up with a standard way, but I\'ll
tell you from practical experience it\'s going to be very difficult.

DR. KATZ: Is this for discussion or yes or no? It sounds like it\'s
discussion.

DR. STERN: Your opinion about more specific instructions and
standardization are needed should this product be labeled.

DR. KATZ: Obviously it was curetted sufficiently that 33 percent of the
people didn\'t have any lesions. I don\'t think I agree you\'re not
going to be able to tell somebody exactly how much. It\'s incredible to
me that bleeding wasn\'t present and people had no pain by the amount of
curetting because 33 percent were cured. But I guess it should be better
standardized, but I don\'t see how it could be in defense of the
sponsor. I don\'t see how they would be able to say curette only very
little.

DR. SAWADA: I have to agree with Dr. Katz. I can tell you that the
limiting standard for curettage is going to be my patient\'s pain factor
or perceived pain factor. It would be very difficult to figure out a way
to standardize millimeter depth that you need to take off of the basal
cell. So I really don\'t have any good recommendations as to how to
standardize that for the insert.

DR. STERN: I\'ll make one other brief comment in terms of direction. It
seems like the evidence we have is without a great deal of information
about local analgesia. This is probably my own misperception but sort of
an advantage of this is doing it without Xylocaine. As I recall from the
old days of a variety of PDT-like agents or agents that give acute
phototoxic reactions, as does methyl ALA, that including myself,
although I\'ve never used ALA, it burns like mad when you\'re doing it.
Now, perhaps your patients are more stoic than I am, but it happens with
tar, with UVA. It happens with almost any phototoxic agent that you\'re
giving in this short period of time, enough of a dose to get the kind of
result you\'ve had. Maybe this ALA is different and we won\'t go there.

But I wonder whether ‑‑ at least my patients, you can barely get a
curette near them without them wanting ‑‑ I don\'t ever curette someone,
even superficially, without Xylocaine anesthesia. I mean, I think that
would be considered outside the standard of practice in at least Boston.
So I wonder if part of what might be helpful are really for the
committee to consider whether in helping to standardize this ‑‑ I mean,
I hate to have the standard being curette till they yell.

(Laughter.)

DR. STERN: It\'s not good for the patient and not a uniform endpoint
because pain thresholds vary so much. I do think we need direction and I
wonder whether we really want to be going for an agent that is sort of
implied, oh, good, you don\'t have to give local anesthesia.

DR. DRAKE: I\'m not sure but what this question shouldn\'t come later in
the discussion. The reason I say that is I think the preparation will be
determined a little bit by how effective one thinks this product is and
what conditions you have to make it effective.

Earlier I asked the question about how deep this particular light source
went. Frankly, with a lot of PDT, the limiting factor is not the
photoactive compounds that you can attach to your target. The limiting
factor is how deep you can get light to penetrate through whatever
mechanism you want to go through. For example, there\'s some very good
potential PDT for lung tumors. The question is how do you get it into
that area of the lung. There\'s some potential stuff on bladder tumors,
but it\'s pretty easy because you can put the light source right up
through the urethra and get the light right where you need it, next to
the source.

So the preparation I think, if you\'re prepping a big, old nodular,
you\'re going to have to debulk it because this light goes 4 to 5
millimeters I think. Isn\'t that about right? So it\'s only going to go
so deep. So you\'re going to have to think about the efficacy of the
whole product before you begin to talk about how to prep it because if
you\'ve got a thick nodular BCC, you\'re going to have to debulk it.

And I\'m with Rob. If somebody comes at me with a curette without
anesthesia, I\'m going to holler like a stuck pig. I don\'t want anybody
with a curette after me without anesthesia. I\'m a coward. So I think
you\'re right, Rob. I think in some communities ‑‑ because we\'re from
Boston and maybe we share that.

But I think your issue here is prepping the lesion for efficacy and
efficacy means you can\'t have too thick a tumor or the light wouldn\'t
get there even if you decide to approve this product.

DR. STERN: Sharon.

DR. RAIMER: I don\'t really have anything further. I think Lynn\'s point
is good. You\'re going to prepare a superficial basal cell differently
than a nodular basal cell. That\'s a very good point I think.

DR. STERN: And in your experience?

(Laughter.)

DR. RAIMER: I\'d want Xylocaine too.

DR. STERN: I was asking our biostatistician.

(Laughter.)

DR. SCHMIDT: I never saw the lesion preparation instructions from the
company in the first place to comment. But my feeling is that, yes,
there should be some fairly specific directions or guidelines on this.
But like I say, I would like to have seen the lesion preparation
instructions so I could comment.

DR. STERN: This is not a question but a clarification. Wasn\'t there a
pictogram somewhere in this red book, or was I hallucinating? I just
couldn\'t find it. Just tell us what page.

DR. MORRIS: Yes, there is one and it\'s the same as the one that was in
the investigator brochure. We also had a video that was distributed to
all the investigators in the trials.

DR. STERN: I\'m not talking about the facial one. The little pictogram.
I just couldn\'t find it now.

DR. BRAATHEN: Page 21.

DR. STERN: No, no, not the facial one. I remember a pictogram.

DR. MORRIS: It was in the presentation this morning. Slide 44.

DR. STERN: Data overload. Thank you.

Did you have other comments, Jimmy?

It\'s a slide we saw during the day which I confused. Slide 44 in their
presentation.

Yes.

DR. KING: Relative to preparation, it seems to me that the indication to
use it is the diagnosis of basal cell to begin with, and it seems to me
that if we had the depth like you do for melanoma, saying this is a
so-much thick or depth lesion, then the preparation would follow about
whether you even have to debulk it to get what Lynn is talking about,
how deep does it go. So that\'s why I was having the thought rolled up
into curettage and photodesiccation. You really do need to know the
tumor depth to know how far it\'s likely to go because your basement is
still flooded. Your first floor is okay, but if it\'s still down in
there, you\'re going to have to make the light go deeper.

DR. SCHMIDT: Just to have this little picture I don\'t think is adequate
to ensure consistency.

DR. STERN: I believe you\'ve heard from the committee the idea that
information is helpful in guiding clinical practice about things that
are intimately related to a drug and device. So you\'ve got a triple
header here. It\'s procedure, drug, and device that are all together.

So let\'s go on to question 2, which is a two-part question about
efficacy. Please discuss the adequacy of outcome measures as well as the
number of patients and lesions to assess the efficacy of MAL-PDT in the
treatment of nodular basal cell carcinoma for, first of all, 6 months
post-treatment by histology only, not clinical, in two pivotal studies,
no follow-up available; and then, B, 2-year clinical follow-up available
in one open-label, randomized study and one open-label non-randomized
study.

DR. WILKIN: If I could just make a quick comment. On the no follow-up
available, that\'s not meant to be pejorative. This is where the lesions
were completely excised. So it wasn\'t really meaningful to then look
for recurrence in that setting.

DR. STERN: Yes. The one issue ‑‑ actually I\'d particularly like to ask
Lloyd King\'s advice about this ‑‑ is in looking at the 3-month
excision, the question is, how good is breadloafing ‑‑ I guess there are
two sequential questions, one particularly from a dermpath ‑‑ a
breadloaf specimen. What is the likelihood it would have picked up a
recurrence, should it exist at least histologically?

And the second is I\'m not sure that even histology at the time of an
excision necessarily proves that that tumor wouldn\'t have recurred so
soon after treatment because, after all, these are tumors that undergo
proliferation and it only takes one residual tumor cell to have a
recurrent tumor.

But could you perhaps give us some idea of what you think the
sensitivity of breadloafing is for the presence of histologic tumor 3
months after a procedure?

DR. KING: Well, I\'ll actually refer to the presentation earlier for
Mohs in the sense of vertical sections. You only look at about 1 percent
of what may be a positive margin. Oftentimes for medical-legal reasons,
you waffle and say the margins are free in the plane of the section. So
that means you\'ve got a 1 in 100 chance type thing.

In general, when we look at tumors like basal cells, you have a 10
percent error of artifact just cutting, say, 7 or 8 sections
sequentially into the block. And if an experienced clinician calls it a
basal cell and you don\'t see it or anything like a tumor, you call it
the bumper. If they see a bump and you don\'t see a bump, you keep
going.

Directly to the issue of breadloafing, you have about, in my experience,
a 30 percent chance at the worst to about a 10 to 15 percent chance of
missing small foci without immunoperoxidase with cytokeratin stains. As
a matter of fact, the Mohs surgeons, when they\'re really nervous, send
their specimens to us to do the immunoperoxidase to miss these small
foci which may be thought of as, say, the root of a hair follicle or
other kind of things. So they\'re indeterminate. Even with
immunoperoxidase, you may miss small foci. So I would think your chance
of error is somewhere between 10 and 25 to 30 percent in breadloafing.

DR. STERN: Michael.

DR. BIGBY: Could the FDA just clarify to which studies are they
referring in part B of this question?

DR. VAUGHAN: We\'re referring to study 303 for the open-label,
randomized study and to study 205 for the open-label, non-randomized
study.

DR. STERN: Shall we go around and start with you, Jimmy, about the
adequacy of these studies to demonstrate the efficacy of this product
for nodular basal cell?

DR. SCHMIDT: I thought that the numbers were small and the recurrence
rate was high, but I think that it does show that there was efficacy in
both of the studies.

DR. TEN HAVE: I agree. It sounds like it\'s more of a clinical debate as
opposed to a statistical debate. The statistics basically say yes, there
is efficacy. They\'ve reached statistical significance. The question is
are the differences that we see clinically significant compared to the
costs of curettage and all of what else the photolight therapy entails.
So it sounds like it\'s a race between cryotherapy and this new therapy
in my mind.

And the non-inferiority trials. 303. Are they part B? Are the
non-inferiority trials part B?

DR. VAUGHAN: The open-label, randomized study versus surgery was a
non-inferiority trial. The one open-label, non-randomized study was just
an open-label, non- randomized study.

DR. TEN HAVE: So 303 was with cryotherapy?

DR. VAUGHAN: No, it was not. Surgery.

DR. TEN HAVE: Oh, surgery. So you\'re not including cryotherapy here?

DR. VAUGHAN: No.

DR. TEN HAVE: Can I ask why?

DR. VAUGHAN: Because the indication in the studies were geared toward
nodular BCC and based on the efficacy and safety of the nodular
indication, then we would look at the one open-label study because
usually we have one trial and then the study should be replicated by a
second trial. The superficial was a non-inferiority study and that was
just one study submitted.

DR. TEN HAVE: So it\'s basically the cryotherapy trial was not the right
indication.

DR. VAUGHAN: Right. It was not one of the pivotal studies.

DR. TEN HAVE: It was not the right indication then?

DR. VAUGHAN: For how the drug was developed, it was not the indication
we were looking at.

DR. TEN HAVE: So we\'re supposed to ignore it? Are you essentially
saying we\'re supposed to ignore that cryotherapy trial for this
discussion?

DR. STERN: Well, as I understand it, it wasn\'t of nodular basal cells.
So since this question is about nodular basal cells and they clearly are
different, as was the comparator therapy, I think for this question, we
would certainly not consider that relevant data.

DR. TEN HAVE: So relative to the surgery, then it\'s not doing so well
in terms of long-term recurrence rates.

DR. STERN: I guess I would ask the agency ‑‑ as I think you\'ve pointed
out very well, one could interpret this, does adding PDT to the regimen
described have some additional benefit versus ‑‑ it clearly makes
significance even in these small trials versus sham PDT and curette. Or
are you asking it as you, I think, suggested? In a clinical sense, is
this enough efficacy that you would, in fact, bring it up with your
patients? Or do you have enough data to make a judgment that you would
be comfortable taking these data forward to your colleagues and patients
and saying, this is the situation with this and, in fact, it\'s worth
entertaining, I\'m confident of what the data says, and the second part,
it makes enough sense that it really makes sense to use? Which is the
agency looking for? Or both?

DR. WILKIN: Well, here we\'re actually interested in the outcome
measures, the adequacy of the outcome measures. Then we have a question
that comes up next, which is has adequate evidence been presented to
support, and then it says primary indication, but really we mean
first-line therapy.

I have to say that we\'ve approached the evaluation of this NDA with the
notion that we would look first at nodular, and then winning on nodular,
we would then look to superficial. That was sort of the algorithmic
approach that we had.

I think what we heard today is that looking for a niche, which I think
is fair ‑‑ I mean, looking at the overall data set and trying to make
the assessment, but is there another way of looking at that? You could
construct question 2 also to be in the treatment of, and then again,
whatever niche indication that the committee would be interested in.

DR. RAIMER: To me the numbers do seem small to have a lot of clinical
confidence in them.

DR. STERN: I guess, in terms of interpreting the data, I would take Dr.
King in terms of part A, the excision data, and say, well, I would
expect that the true number of non-cured tumors would go up 10 to 30
percent in each group, and if they were different between any group
studied, that means that the absolute difference between the groups
would go up proportionately.

And I would say for the 2-year data, similarly, since we haven\'t seen
any data to the contrary, whatever the differences are in recurrence
rates, at 2 years we would expect that absolute difference to increase
over time because all the data for every modality shows the same upward
trend in recurrences as time goes by. So, if in general, at 5 years
recurrence rates are about twice they are at 2 to 3 years, I\'d expect
both absolute recurrence rates to double, and therefore if they\'re
different, the difference between them to increase by the difference
between 2X minus 2Y, if X and Y were the first two recurrence rates.
That would be my interpretation.

I think this is a small data set that I don\'t find particularly
encouraging as something I would want to introduce in my own patient
practice.

DR. SAWADA: Again, I agree with my colleagues in the sense that it\'s
such a small data set. But the question is efficacy, and I thought it
did show efficacy.

DR. KATZ: I think this question is not directed to whether we think the
drug works or not. The question is discuss the adequacy of outcome
measures. So I think on this question ‑‑ correct me if I\'m wrong, Dr.
Wilkin ‑‑ it\'s not to give our opinion on how good the drug is or not,
but how adequate the outcome measures are. Is that correct?

DR. WILKIN: In a word, yes. The timing and then also how one is looking.

DR. KATZ: So everybody has been discussing whether they think it\'s good
or not or how they would use it, but on this, adequacy of outcome
measures, it seems to me that they did adequate outcome measures. But
that\'s to me. We rely on experts like Dr. Alosh. Dr. Alosh, are these
the measures that you were discussing before statistically? You pointed
out some inadequacies in it.

DR. ALOSH: Right. We presented the results for histology which is the
sponsor\'s results, and then we looked to clinical and histology.

DR. KATZ: In these studies we\'re discussing right here.

DR. ALOSH: Right, the pivotal studies.

DR. KATZ: So I\'d have to they\'re not adequate based on our expert
opinion around the table. I think they tried to do an adequate job, but
based on the doubts raised, we have to take that into consideration.

DR. ALOSH: Let me clarify. For the non-inferiority trials, as I pointed
out, really we did not put much emphasis on those because the protocol
did not come to the agency for comment. I cited what I have seen as
shortcomings in terms of there is no vehicle, there is no
non-inferiority margin prespecified. For the pivotal studies, the
results for histology, and then contrasted to the clinical and
histology, you could see the response rate is lower.

DR. KATZ: So my answer would be, based on that, no to this question.

DR. KING: I\'m struck, by thinking it through, that I guess you come
from a bias of being a dermatopathologist that having a clinical is
great, but last we heard, diagnosis of cancer is under the microscope.
So I would have liked to have seen the clinical and histology on each
one of them type thing in the pilot studies, and given the figure 4
where they\'re showing the tumor selectivity of the MAL cream, you
wonder why at the time of, say, the second treatment, simply using a
black light type thing looking to see if there are foci still there and
then, say, doing a 2-millimeter biopsy or something like that because in
the last 5 years, what we\'ve been doing, we\'ve been writing tumor BCC
nodular, comma, with infiltrative at base. So you have 90 percent of
something that\'s a nodular, scrapes like jelly. Yet, at the bottom
there are these things that look like the continent of Africa or South
America. In hindsight, those are the ones that recur.

So I think that trying to define, in general, does it work ‑‑ how many
of these are mixed tumor types because you can have superficial with a
nodular component, you can have a basal with a sclerosing component,
infiltrative features. So I would like to have seen that kind of thing
rather than saying, oh, it\'s clear because at 10 years there are still
going to be a substantial number of recurrences. Yet, you pull the
slides back and all that and usually it\'s the lawyer sniffing around.
The answer is yes, based on that particular section, it\'s all gone, but
that\'s less than 1 percent of the total.

So based on what Dr. Katz said and I would say, I would rather have seen
the clinical, the histology, and the simple add-on, doing the light at
the time of second application to see why it may be needing a second
treatment.

DR. BIGBY: Sometimes it just really gets to be very frustrating to me to
hear things that are so simple become so difficult. Everybody here has
already said there are more than 2 million cases of basal cell in the
United States a year. So it\'s a common thing. It\'s not hard to find
patients for this kind of study.

So what was presented in (a) really is a surrogate endpoint of whether
this treatment compared to a placebo cures the patient. It\'s a
surrogate because what they did is they took what was left in 6 months
and they breadloafed it, and we saw that that is not an entirely
sensitive method to determine whether or not they were cured.

So if you had unlimited resources and very smart people doing this, what
you would really do is to do a controlled trial of the treatment versus
placebo and follow them for 2 to 5 years, and you would really find out
what the recurrence rate is after treatment and after placebo. So I
think that the answer to this question of is the outcome measure
adequate in section (a) is clearly no, and I don\'t think that anybody
can conjure up an argument to make it so.

In terms of the outcome measure in the sort of part (b) section, maybe
because what you have there is, at least in the surgical comparison
trial, groups of patients who were treated and followed out over a
period of time to see who has recurred. I think that that data now goes
out to 2 years for some, if not all, of the patients and it is a more
reasonable approximation for what the clinician really wants to know.
And the same thing can be said for the open-label study in that you
treat the patients and you see what happens.

So the answer to the question about is the outcome measure adequate,
it\'s clearly no for (a) and it may be for (b) but (b) has a lot of
other problems in terms of study design that I\'ll sort of talk about
when we try to answer question 3.

DR. DRAKE: Well, I agree with Michael. How could something so
straightforward become so complex? Nonetheless, every time we try to
look at a study like this, that\'s exactly what it ends up being. It\'s
very complex.

I would very much like to see something like this available for our
patients. I think we need something like this.

Are these measures adequate? I have to say no to part (a). What I\'d
like to suggest ‑‑ and maybe they\'ve got enough data hidden in all this
stuff we\'ve heard today because the company has clearly done a lot of
work. Maybe the data is in there. Maybe they can tease it out because I
think the real utilization of this is going to be in superficial because
if not, you\'re going to have to have a lot more information, in my
opinion, about how much to debulk. How thin do you need to make that
tumor before you can get the light to where you need to go? Because if
people get it out there and they don\'t debulk it and they\'re treating
nodulars, I\'m not sure they\'re going to get this good a result because
the company spent a lot of time, in my opinion, trying to tell people
how to debulk and clinical investigators tend to do what they\'re told
and they do debulk. In real practice, will that happen and how do we
advise clinicians on how much to debulk it, I don\'t know.

So I guess I would say on the surface of what I\'ve seen today, the
answer to (a) is no. You might be able to tease some stuff out if they
could take a subset of their data set to perhaps make an indication even
more narrow. So that\'s a long answer that doesn\'t really tell you
much, and I\'m sorry for the folks at the FDA. I can\'t give you a
better opinion than that.

I\'m torn between really wanting something like this and being nervous,
as Lloyd pointed out, that the second you turn it loose, unfortunately
you\'re going to have people who don\'t know the first thing about
treating skin cancers out there treating people.

To me we\'re not here to answer the money or time or any of those
questions. We\'re here to answer is it safe and is it effective. Those
are the only two things I think this committee is charged with. I don\'t
care if takes them 6 hours and I don\'t care what the cost is. The
marketplace will sort that out.

What I am very concerned about is the patient. If they go in and get a
skin cancer treated and they think it\'s treated and if it isn\'t
treated, then you could end up with a rodent ulcer. So I don\'t want
that to happen to anybody.

On the other hand, I think many people are over-treated. They spend days
in Mohs therapy and what else when they don\'t actually need it and
there are some places where it\'s just not indicated. And there are
places where we don\'t have good therapy.

To the company, I would recommend highly that they go back and look and
see if they have a subset of patients in there that you could frame this
around that would be straightforward and a straightforward indication
that would help some of our patients.

MS. KNUDSON: Well, I have to say as a consumer I\'m totally confused. I
am not a biostatistician. I would love to have had something presented
in a much more reasonable, orderly, and understandable way, and if I
were a patient being asked to consider this new modality as opposed to
other modalities, I would probably say no, more because I was totally
confused by all of the information I was given than for any other
reason.

DR. STERN: Well, I\'m sorry I\'m so poor at describing the alternative
therapies.

DR. TAN: Well, for question (a), I think it\'s mostly no. I still don\'t
understand why the clinical response ‑‑ that\'s sort of the standard for
any cancer drug ‑‑ is not used to assess the response rate. I think that
is probably the more appropriate measure for the outcome and in
conjunction with the time to recurrence. Ideally you want to have
probably both of these as endpoints. But we live in real life, but it
just would probably take forever, too long to have adequate evidence
based on the time to recurrence.

So for the second part of this, it\'s probably yes. You should have some
of this. It\'s a compromise. So it\'s just a compromise. I think it is
yes to the second one.

DR. RINGEL: In terms of the first study, I think this study is as good
as you can do a histologic study. I would have liked to have seen more
patients. There were 70 and 80 lesions in either group, which isn\'t
bad. But you can\'t ethically take a placebo group and tell them to wait
5 years and see what happens. You just can\'t. So you can\'t do this
study, as far I\'m concerned, better than it has been done. I think that
asking a patient to wait 6 months is a lot.

Now, could they have done something better than breadloafing? I need to
ask our local histopathologist here. Could they have taken these
specimens and done a Mohs processing on them and gotten a better ‑‑ is
that technically feasible to do Mohs processing on that?

DR. KING: Yes.

DR. RINGEL: So that would be certainly one way to make the study better.
So at least you could have looked at all the margins. It would have
certainly helped.

But the problem with the histopath studies is that if the margin is
negative, it can still recur, and if the margin is positive, it may not
recur. So you\'re always limited. As much as it\'s nice to say, oh,
well, I have a test, I can see if a cancer is there because I have the
test, if the test isn\'t 100 percent sensitive and specific, it may not
be such a great test.

What I\'d like as a clinician frankly is the other study, the long-term
study. I want to know following that patient for 5 years, is it
recurring. Frankly, if there are a couple cells left there
histologically but they\'re not recurring clinically and they\'re just
going to sit there for another 10 years and the person is going to die
of something else, frankly, I don\'t care. I want to know how did that
patient do in 5 years. I would like to see two of those studies carried
out for a long period of time. Yes, I\'d like to see the other
histologic study, but what I really care about are long-term results.

DR. STERN: As we go to the next question, I want to ask, so we won\'t
get into semantics here, the agency for a couple of clarifications on
this question. The question is, has adequate evidence been presented to
support a primary indication for the treatment of basal cell carcinoma
for this product? I\'d like you to define primary and say whether
you\'re asking us here about nodular only or nodular and superficial
before we go around. So could you help me with that?

DR. WILKIN: Well, of course, we sometimes like to modify questions a bit
after we\'ve heard discussion. So I take your point that this could be
subdivided into different sort of niche indications.

What we originally meant by primary was first-line therapy.

DR. STERN: That\'s fine. Just so we know what you meant by that.

And how about the basal cell carcinoma or nodular basal cell carcinoma?

DR. WILKIN: Sure. I think that it can be overall basal cell carcinoma,
if the committee wants to consider that. We looked at nodular primarily.
There are some data, of course, for superficial. I think we spoke to the
recurrence data set. So I suppose it could be either nodular or
superficial or nodular and superficial that would be the options for the
committee.

DR. STERN: With the agency\'s permission, which I think might speed
things along, this is a yes/no and I would ask people, first of all, to
say do they believe that there\'s adequate efficacy information for this
as a first-line therapy for basal cell carcinoma. If the answer to that
is yes, then they should specify whether it\'s, based on the evidence,
nodular, nodular and superficial, or basal cell carcinoma not otherwise
supervised that they believe the efficacy information supports. Is that
acceptable to the agency in terms of how to ask this question? Because
I\'m afraid we\'re going to get into this, oh, I\'d love it for
superficials, but I wouldn\'t use it for nodulars.

So the question is first-line therapy for basal cell. I guess, if so, do
you believe the evidence restricts it to any subtypes. Maybe that\'s an
easier way of saying qualify it based on the evidence.

Yes.

DR. BULL: I would remind the committee once again that you have to make
your deliberations based on the data you have on hand. There\'s a
question that comes later that does address whether or not further
studies or if you want to ask for some subgroup analyses, but there\'s
opportunity to ask for more exploration of where you see the need or
potential use of the product based on what you\'ve reviewed.

DR. STERN: So data-driven, not what we\'d like, but what we see.

Jimmy.

DR. SCHMIDT: Yes for nodular BCC and superficial BCC, and I would
exclude morpheaform, the other types.

DR. TEN HAVE: Being a biostatistician, it\'s probably not appropriate
for me to comment on this, but I\'m going to try anyway.

Just to clarify in my mind what the picture is, again, the distinction
between superficial and nodular has an impact on what studies we
consider. I\'m going back to the point of conversation we had earlier.
It seems to me, again, that the cryotherapy versus MAL trial was the
superficial BCC trial. Right? And that\'s key in my mind. That\'s where
MAL did well in the long-term recurrent rate department, and I\'m going
to say because of that I think superficial is where it should be
targeted.

DR. STERN: So if I understand you, it was yes, superficial only.

DR. TEN HAVE: Right.

DR. STERN: Thank you.

DR. RAIMER: I\'m fudging a bit too. For me it is yes, but it\'s only for
those lesions that are unsuitable for other available therapies.

DR. STERN: I do not think that I could support this as a first-line
therapy based on the evaluable evidence. So I don\'t have to specify
what type.

DR. SAWADA: I too would not consider this as first-line therapy. I\'d
have to say no.

DR. KATZ: No.

DR. KING: As a primary therapy, I have to go with no. I think that the
sponsor has already eliminated sclerosing and infiltrative and so forth.
So that\'s not there. So the answer would be no if you mean primary
therapy.

DR. BIGBY: I would also say no, and I\'d just like to remind the
advisory panel that what we\'re looking at is two randomized,
placebo-controlled trials with basically 30 people in control and active
arms in two separate studies and a difference between placebo that has a
confidence interval that at the lower end was 18 percent in one study
and 24 percent in the other.

It never ceases to amaze me how limited the amount of efficacy evidence
that\'s actually presented is. I think as long as we sort of keep
advising to approve treatments where this is the level of evidence we
get, we\'ll always get this level of evidence.

DR. DRAKE: As a primary, I\'d have to say no. A subset, I have a
different opinion, but I\'m going to leave. I apologize. I told you I
had to leave early. I might have a different opinion on a subset, but as
a primary I\'d have to say no right now.

MS. KNUDSON: I also will say no.

DR. TAN: I will say no, not as first-line because we really need to
reconcile the 6 months\' efficacy with the recurrence rate.

DR. RINGEL: No.

DR. STERN: May I ask the agency? Is question 4 still relevant, given
what we\'ve said in response to question 3? There were 3 yeses and 9
noes in response to question 3.

DR. WILKIN: I think for comment we may eventually have more studies, and
to keep from coming back to the committee, what we\'d, I think, like to
hear is, is there something that you would suggest would go in the
indication section sort of to frame, just some general kinds of
comments?

DR. STERN: I don\'t know how we can do it with the data we have.

DR. BIGBY: Wait. I really don\'t understand this question. I don\'t
understand what it is that you\'re asking.

DR. WILKIN: Okay, fair enough. What we are asking actually has some
basis in what we\'ve heard around the table today. You spent a lot of
time talking about standard of care and what you believed to be the
rates of success with other modalities. Basically the question is those
other modalities ‑‑ is there a role for that information in labeling
should this product eventually be approved for primary all basal cell
carcinomas or any particular subset. So it\'s sort of hypothetical but
in that construct, would you see a role for that information about those
other modalities crafted into labeling? That\'s the basis.

DR. STERN: With that context, this surprises me because every new label
I see basically summarizes the results of the studies that were accepted
in going into the label, and clearly whether there\'s an active
comparator or a placebo comparator, those data are presented as part of
at least all the package inserts I see coming rolling out. Of course,
the information is useful and our problem is that there\'s not enough
information yet about this drug relative to comparator.

DR. BULL: Not being a dermatologist here, but in the discussions I\'ve
participated in with the division, as we were trying to craft the
questions, I think there was a concern that we bring to you all as our
experts who are in clinical practice as to contextually where this
therapy fits in or if you have a therapy that may be viewed at least by
the existing body of data as potentially less efficacious than the
\"standard of care.\" I think there has been comment made that that body
of data is probably not the best, but if there was any comment the
committee might provide as to how that might be given. We do have some
studies that did compare to surgical treatment.

DR. KATZ: Related to that, when you say the data is not adequate,
nothing is perfect.

DR. BULL: Right.

DR. KATZ: But the fact is that in the literature repeatedly we see the
same numbers. As was pointed out, people don\'t report sometimes if they
have poor results, but generally speaking, what is in the literature is
fairly close and it also is consistent with what many of us see ‑‑ I
didn\'t poll everybody of my colleagues ‑‑ in the office. So I would
disagree that, oh, the data we have on recurrences, we can\'t believe
anything about it. That impression should not persist. We have a pretty
good idea of how frequent recurrences are.

DR. STERN: Other comments on 4? Michael?

DR. BIGBY: So if I understand this correctly, what I would say is that
the best information that one could convey to our colleagues would be
the results of head-to-head trials in terms of how it compared to
placebo, cryotherapy, and surgery. That would be the advice that I would
give people because based on available data, that\'s the best data that
there is.

DR. STERN: Question 5, safety. Please discuss the adequacy of the safety
assessment, including the contact sensitization assessment and the
adequacy of data on recurrence rates. I would say that we\'ve answered
the issues of the adequacy of data on recurrence rates ad nauseam and
would prefer to just address the issue of contact sensitization. I\'ve
forgotten where I was last time going around the room, but I think I\'ll
start with Eileen.

DR. RINGEL: I think they\'re almost there but not quite. I\'d like to
see some longer-term studies done with patch testing in the way that
people are going to use this. For example, it doesn\'t seem that after
four treatments people have a significant rate of contact sensitization,
at least clinically, but people will theoretically keep on getting basal
cell carcinomas for years to come and they may potentially be exposed
over and over and over and over again. So it seems to me it might be
relatively easy to do a study of the 3-hour application, wait a day, a
3-hour application, wait. In other words, see how many 3-hour
applications you can get until you do get contact sensitization, and
that might be useful information, more in the way that it will be used
clinically.

And the second issue is I would want to make sure that whatever gloves
physicians are using, that this agent cannot penetrate it. So I\'d like
to make sure that this is good for latex gloves, vinyl gloves, the rest.

DR. TAN: Yes, I would defer this to our physician scientists because
there was debate about whether this is relevant.

MS. KNUDSON: My concern was the sensitization and irritancy that were in
the normal subjects. 52 percent of them had reactions with long
exposures. So I second what Eileen said in terms of the health care
provider.

DR. BIGBY: I\'m actually satisfied with the sponsor\'s assessment of the
risk to patients. I do share the concern about making sure that health
care workers protect themselves from this, especially if they are going
to be doing this frequently.

DR. KING: Having wrestled with the FDA over orphan drug indications for
diphencyprone for about two-and-a-half years, it becomes one of the
issues of is the chemical available in the environment so there\'s going
to be cross-sensitization. I recognize the argument that benzoyl
peroxide and a number of agents like preservatives are available, and
they\'re approved for over-the-counter. I think that\'s a little bit
different from saying you\'re going to sensitize somebody to an
endogenous ALA which all cells contain in the mitochondria, et cetera.

Actually I was hoping they would turn out to be that the MAL would be a
unique chemical and we could use it for alopecia areata as an
FDA-approved drug.

Having said that, 2 percent of a big number is still a big number, and I
am concerned. I applaud their efforts. I\'d just like to know a little
bit more about that. So you can\'t get a drug approved, as I know, over
the counter if you have a 2 percent incidence of sensitization for
fragrances, et cetera. So I\'d like to see a little more data about
that.

DR. KATZ: Yes, I think the safety assessment has been adequate. It is
somewhat worrisome on contact sensitization of that percentage of
people, but as was properly pointed out, if you\'re treating some skin
cancers and somebody gets an allergic contact dermatitis, then you treat
it. It\'s really no big deal. We treat contact dermatitis in the office
during the summer multiple times a day, and that person would not be
appropriate for further treatment with that. So that doesn\'t bother me.
What bothers me is the recurrence rates and the ineffectiveness
relatively of the drug. But I think adequate safety assessments were
done, and I think appropriate comments were made on it not being a
terribly worrisome thing if the patients developed a contact dermatitis.

DR. SAWADA: Again, I noted the high rate of contact sensitization with
the patients. Again, that\'s good and well. I think what the company
provided was good information.

But again, I echo Eileen\'s concern if I were the one who became
sensitized to this in giving it. I worry about my staff and myself. So
I\'d like to see a little bit more data on that aspect and what kind of
protective measures we need to take to avoid sensitization.

DR. STERN: I have no comments on sensitization.

One thing that I did not see in the safety data ‑‑ or perhaps I missed
it ‑‑ is the persistence of photosensitivity, since there is lots of red
light when you go out and a lot of these lesions are in exposed areas.
It\'s visible light, and what about inadvertent exposure and
sensitization to other sites? Have you done in normal skin, in fact,
MPDs to look at if you apply this cream and you irradiate it on normal
tissue, whether or not you get what the MPD is, how long an equivalent
of sunlight? So I think those data, if they exist, certainly need to be
shared. When you put ALA on normal skin, you get photosensitization.

I understand that you\'ve shown pictures that you don\'t see
fluorescence on mice where it\'s not applied, but I\'d like to see some
actual human data with application of the agent to normal skin. But that
may be there. And then if you\'ve got it covered, the agency will pay
attention to it.

DR. KATZ: I also wanted to add the emphasis. We should put a lot of
priority on the clinicians not seeing problems with the drug. So we may
get sensitization with the sensitivity studies, but when so many
patients have been treated and they just haven\'t seen contact
dermatitis, that would be a very obvious thing. So we must put a lot of
credence on that for this aspect of the problem.

DR. RAIMER: Yes, I agree with others. I don\'t really have things to
add. But I do think the possibility of the cross-sensitization with the
ALA needs to be monitored continuously.

DR. SCHMIDT: I love to see a contact dermatitis to 5-FU and some of
these other things. I think you get your best results. So actually, to
kind of spice the pot a little bit with a contact dermatitis is good. So
I go along with that they did show the adequacy of the recurrence rate
and the contact sensitivity assessment.

DR. STERN: Now we go on to question 6, which is I believe a voting
question. This question is, based on the safety and efficacy data, does
the committee find a favorable risk versus benefit balance to support
approval of this product?

DR. SCHMIDT: Why do I always get to be the first?

(Laughter.)

DR. SCHMIDT: This is a tough one. No, no. I\'m not trying to weasel out.

I\'d say yes.

DR. TEN HAVE: Do I get to vote?

(Laughter.)

DR. TEN HAVE: Given my past comments, I would vote yes for the
superficial indication.

DR. RAIMER: How are we voting? Are we just voting in general? We\'re not
voting for specific types of tumor, are we? We\'re just voting on the
data that we have, do we think it\'s adequate.

As much as I would like to have it for superficial, at the moment I\'m
not sure that the data is adequate. I\'m going to vote no.

DR. STERN: No.

DR. SAWADA: No.

DR. KATZ: No.

DR. KING: No.

DR. BIGBY: No.

MS. KNUDSON: No.

DR. TAN: No.

DR. RINGEL: No.

DR. STERN: The next question is additional studies. Please discuss
whether any additional studies may be needed and whether these studies
might be conducted after approval, which is hard after the prior
question to ask, although I suppose sometime in the far future. Perhaps
we could put it, please discuss what you might think would be useful
pre-approval and post-approval studies, should the agent eventually be
approved. How about that for a question?

I think we\'ve already made lots of suggestions, so it would be
additional things that either you as an individual have not said or have
not heard other people say. With that, I would say I don\'t have
anything to say that I haven\'t. I can\'t think of additional things
that someone hasn\'t raised as additional studies, ways to design them,
et cetera.

DR. SCHMIDT: I agree with you.

DR. TEN HAVE: Same here.

DR. KATZ: Well, the drug has shown to be more effective than placebo,
and I would think that if the sponsor could show, so to speak, a niche
where we would say, oh, yes, that\'s a place that we could use in that
patient as advantageous over what we have available, I think that would
be very interesting.

DR. KING: I think that I have a two-part answer. One, I\'d like to see
larger numbers simply because for a million-plus people, that\'s not
very many numbers. I guess in the real world it\'s hard to do these.
They\'re expensive and time-consuming.

But I\'d like to see something that when they define the type of basal
cell, they put in the category of nodular by itself or solid with or
without infiltrative features and so forth and then give the depth. We
know that\'s an important part of the melanoma. And I\'d also like
ulcerations. I\'d like a more precise description as a
dermatopathologist of what you start with. At some point you would have
clinical and the pathology or histopathology of the lesion, and then for
those that fail, I\'d like to see a histological evaluation to correlate
with the clinical. That would also include at the time of applying it.
Since we\'re saying that MAL is tumor-specific, just shine the black
light on it or confocal fluorescent microscopy and determine if why
it\'s persisting is, instead of just having a nodular, you have then the
heterogeneous tumor which has biologically aggressive features such as
the sclerosing or morpheaform, et cetera.

That may explain in my experience why things come back because
oftentimes you\'ll diagnose, based on a small section, a nodular tumor,
and then when it recurs, it comes back to you. You have to look back and
say that\'s not a nodular. On an excision or the recurrence, you have a
totally different biological appearance, I mean, regression, based on
it\'s no longer just a simple nodular.

So I\'d go for clinical histology and the repeat and then the porphyrin
specificity.

DR. BIGBY: I just think that the problem study for this application
really is the placebo-controlled trial and the fact that they had such
high cure rates in the placebo arm. I think it\'s fairly obvious what
needs to be done in terms of a study to explain that and to sort of
ferret out what in this therapy is the effective modality.

MS. KNUDSON: I\'ll echo all that was said.

DR. TAN: Yes, probably some more studies need to be conducted, by first
carefully looking at the current data and I think a cleverly designed
study, especially taking into consideration keeping the response rate
up, but at the same time keep the recurrence rate down. I think that\'s
the key. Those two things have to be there.

DR. RINGEL: I think that they need to design a study for the patient
population in which it will be used, and from what I\'ve heard today,
mostly that includes lesions of large diameter on the trunk and
extremities in patients who are not surgical candidates because of
bleeding, diathesis, or whatever.

I would not, just as an additional point, use this on the face. I think
that the failure rate that I heard of 48 percent is so high, I think I
would never use this on the face. They can do Mohs surgery. I just
don\'t see the point of it. I just wouldn\'t do it.

The other thing is I think I would make very clear that this is
something that\'s used in patients who are not candidates for surgery.
What I worry about is what many people have said: this is too easy to
use. Anybody can get their hands on this and do it. It doesn\'t sound
like you need a whole lot of training. It\'s going to cost some money,
probably buying, leasing this light. Once you purchase it, you\'re going
to want to get your money\'s worth out of it, and you\'ll be tempted to
use it on perhaps more patients than it should be. So I think we need to
make very clear that this is for patients who cannot, for one reason or
another, be treated by surgery, for large lesions, for bleeding lesions,
not for lesions on the face.

DR. STERN: The final question that the agency has put to the committee
is, as I understand it, a generic one. For future development of drug
products for basal cell cancer ‑‑ in other words, not limited to this
sponsor\'s product ‑‑ please discuss which measures should be the
primary efficacy measures, clinical evaluation and/or histologic
clearing and the time points as well as recurrence rates and appropriate
time points.

Again, I would ask the committee to add things that they don\'t believe
have been covered because I think we\'ve spent a large amount of time
addressing these issues as it applies to this, but in a way that has, in
fact, been very broad-ranging that is generally applicable to what we\'d
want to see for a product for basal cell. So at least I have no comments
to make beyond those that have been made by the committee already.

DR. SCHMIDT: I agree, but I think just in way of review, I think that
when they do the histology, to do the Mohs where you slice it, where you
can see the sides and the base, and then to extend these studies out to
try to get the recurrence rates for like 2 to 5 years because I know
these are going to come up.

DR. TEN HAVE: This is probably a more general question that we actually
asked earlier about non-inferiority trials regarding the threshold of 15
percent. You asked that question before lunch.

DR. STERN: Yes, thank you. I\'m sorry. I guess to me that in powering
studies, I do not consider an incidence/rate ratio of 4 with an
underlying assumption of a 5 percent failure rate in the comparator
group to show non-inferiority to be adequate. Powering a study to
exclude an increased risk of 4-fold higher an incidence, assuming 5
percent in the compared-to therapy, is too high a margin. I would have
to say that if I were powering studies, if the assumed recurrence rate
is as high as 5 percent in the treatment to which the innovator is being
compared, I would want the odds of recurrence at 2 years to be no more
than double. To say to a patient, well, as far as we know, we\'re pretty
sure it\'s not going to be more than four times as much, that\'s not
enough powering in a non-inferiority trial. So to me, when you\'re
talking about a doubling of risk assuming a relatively low risk for the
baseline comparison of, say, 5 percent, that\'s clinically acceptable
because then there are tradeoffs. When you\'re talking I can only
exclude it being four times more likely that you\'re going to have a
recurrence, I don\'t think that\'s adequate powering. Thank you.

DR. RAIMER: I think it\'s very unusual that you see clinical recurrence
of a lesion at 6 months after it\'s been treated. I would suspect that
histologically there are very few cells there even if it\'s going to
recur. So I think it would be hard to demonstrate most of the time
histologically.

I agree with Eileen that you can\'t ask somebody to undergo a placebo
treatment and have a long-term study, and you can\'t expect somebody to
want their lesion excised 2 years after it\'s been removed, especially
if it clinically looks good.

So I think maybe more clinical studies that are maybe not even
placebo-controlled, more long-term clinical studies using this entity,
looking for clinical recurrence and then biopsying if there\'s anything
suspicious at all need to be carried out. I\'d like to see them at least
2 to 5 years.

DR. SAWADA: And I just have to agree with Dr. Raimer. I would want to
see these studies further out.

DR. KATZ: I have nothing to add.

DR. KING: I\'ve said all I really want to say except I\'d like for this
to be approved in principle and just power to study more and have more
patients involved and try to find the heterogeneity.

MS. KNUDSON: I have nothing to add.

DR. TAN: Again, I said before that I don\'t understand why clinical
response is not used. So, therefore, I would like to have the clinical
response to be used. For anticancer drugs, they use this so-called
objective response which is a combination of the histological response
and the clinical observation. So they have several pages of this to
define how they derive that. I think that will be very helpful to design
future trials.

Of course, any trial like this probably, given the high success rate of
the current therapy like the surgery, you always need to consider other
parameters. In this particular example we discussed today, it was the
recurrence rate. For some other products, maybe some other parameter
needs to be considered because in terms of response rate, you probably
cannot really beat the surgery.

DR. RINGEL: I think that the primary efficacy studies should be
unfortunately the one that\'s not controlled but long-term like 303 was,
but carried out at least 3 years. According to the article that you gave
us by Daniel Rowe, 3 years has 66 percent of the recurrences, which is
over half. You can make mathematical calculations at that point. So I\'d
say at least 3 years. 5 would be preferable, but I think 3 should be
enough.

And then because those can\'t be placebo-controlled studies, I think
that it would be nice to have studies like 307 and 308, and I think we
should have both available but the primary efficacy studies should be
the long-term ones, the clinical ones.

DR. STERN: Does the sponsor have any questions or final comments,
questions for the committee before we close?

DR. MORRIS: No.

DR. POSNER: Can I just make one comment?

DR. STERN: Sure.

DR. POSNER: I would just like to point out that the cryotherapy results
are fact. They show no difference. Whichever way you look at them, they
show no difference between MAL-PDT and cryotherapy. That\'s fact.
That\'s not opinion. Really the difference between publication bias and
a randomized, multi-center clinical trial in this fashion are really so
different that we would stand by those results. We do feel that they
should be taken into account in the overall assessment of efficacy.

DR. STERN: Thank you.

And does the FDA have any final comments, questions, criticisms?

DR. WILKIN: I don\'t think any final questions, but certainly we\'re
grateful for not just going through the questions and giving us all the
abundant information there, but as you probably know, we go back over
the transcripts for the entire session, and you had quite a bit of
discussion this morning and then you started again at 1:00. So we have a
lot ahead of us to pore over and we are very much appreciative of the
thought that you\'ve given this. Thank you.

DR. STERN: Therefore, the meeting is adjourned. Thank you all very much,
sponsor, FDA, and participants. Thank you.

(Whereupon, at 3:48 p.m., the committee was adjourned.)