UNITED STATES OF AMERICA

    	FOOD AND DRUG ADMINISTRATION

    	CENTER FOR DRUG EVALUATION AND RESEARCH

    	* * *

    	ONCOLOGIC DRUGS ADVISORY COMMITTEE

    	(ODAC)

    	* * *

    	71st MEETING

    	* * *

    	WEDNESDAY,

    	FEBRUARY 27, 2002

    	* * *

The Advisory Committee met at 8:00 a.m., in the Versailles Room of the
Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Stacy R.
Nerenstone, Chairperson, presiding.

PRESENT:

STACY NERENSTONE, M.D., Chairperson

KATHY S. ALBAIN, M.D., Member

DOUGLAS BLAYNEY, M.D., Member

OTIS BRAWLEY, M.D., Member

PRESENT (Continued):

MASSIMO CARDINALI, M.D., FDA

JOHN CARPENTER, M.D., Member

THOMAS FLEMING, Ph.D., Consultant

STEPHEN GEORGE, Ph.D., Member

JOSEPH IBRAHIM, Ph.D., Guest Speaker

PATRICIA KEEGAN, M.D., FDA

DAVID KELSON, M.D., Member

JOHN M. KIRKWOOD, M.D., Guest Speaker

KENNETH McDONOUGH, Patient Representative

ROBERT M. NELSON,M.D., Ph.D., Consultant

GEORGE OHYE, Industry Representative, Guest Speaker

JODY PELUSI, R.N., Ph.D., Consumer Representative (via telephone)

DONNA PRZEPIORKA, M.D., Ph.D., Member

BRUCE REDMAN, D.O., Member

JAY SIEGEL, M.D., FDA

GEORGE SLEDGE, M.D., Member

SARAH TAYLOR, M.D., Member

HAROLD Y. VANDERPOOL, Ph.D., Constulant

KAREN TEMPLETON-SOMERS, Ph.D., Executive Secretary

ALSO PRESENT:

PAUL B. CHAPMAN, M.D.

KAREN L. GRAHAM

VINCENT LI, M.D., M.B.A.

JOSE LUTZKY, M.D.

STEVEN J. O\'DAY, M.D.

STEVEN ROSENBERG, M.D.

LYNN SCHUCHTER, M.D.

WILLIAM SHARFMAN, M.D.

CRAIG L. SLINGLUFF, JR., M.D.

LYNN E. SPITLER, M.D.

MARTIN A. CHEEVER, M.D.

KENNETH VON ESCHEV, Ph.D.

CINDY JACOBS, Ph.D., M.D.

JOHN THOMPSON, M.D.

WALTER URBA, Ph.D., M.D.

STUART KROLL, M.A.

HEATHER TULLY, M.D.

JEFFREY SOSMAN, M.D.

C-O-N-T-E-N-T-S

Introductions 5

Conflict of Interest Statement 7, 234

Public Comment:

Dr. Lynn E. Spitler 10

Dr. Jose Lutzky 14

Karen L. Graham 17

Dr. Paul B. Chapman 23

Dr. William Sharfman 28

Dr. Steven O\'Day 31

Dr. Lynn Schuchter 42

Dr. Vincent Li 46

Dr. Steven Rosenberg 50

[Trial Design Considerations and Appropriate Patient]{.underline}

[Populations for Studies of Investigational Agents for]{.underline}

[Adjuvant Therapy of Melanoma:]{.underline}

FDA Presentation:

Dr. Massimo Cardinali 56

Dr. Jawahar Tiwari 63

Dr. John M. Kirkwood 74

Dr. Joseph G. Ibrahim 99

Committee Discussion of Questions 169

[IND 2885, Melacine]{.underline}:

Sponsor Presentation:

Martin A. Cheever, M.D. 235

Questions to the Committee 303

    	P-R-O-C-E-E-D-I-N-G-S

(8:12 a.m.)

CHAIRPERSON NERENSTONE: Good morning. I\'d like to welcome to the 71st
meeting of ODAC. We have an interesting morning and afternoon.

I\'d like to start with going around the table and everyone please
introducing themselves. Dr. Kirkwood, if you would like to start.

Please turn on your microphone.

DR. KIRKWOOD: John Kirkwood, University of Pittsburgh Medical Center.

MR. OHYE: George Ohye, nominee as industry rep.

MR. REDMAN: Bruce Redman, University of Michigan Medical Center.

DR. BRAWLEY: Otis Brawley, Emory University, Atlanta.

MR. McDONOUGH: Kenneth McDonough, North Huntington Township, patient
representative and consultant.

DR. NELSON: Robert Nelson, Children\'s Hospital, Philadelphia, and the
University of Pennsylvania.

DR. PRZEPIORKA: Donna Przepiorka, Baylor College of Medicine, Center for
Cell and Gene Therapy.

DR. GEORGE: Stephen George, Duke University Medical Center.

CHAIRPERSON NERENSTONE: Stacy Nerenstone, medical oncologist, Hartford,
Connecticut.

DR. TEMPLETON-SOMERS: Karen Somers, Executive Secretary to the
Committee, FDA.

And we also have participating by telecon. Jody Pelusi, our consumer
rep.

Can you say hello, Jody?

(No response.)

DR. KELSON: David Kelson, Sloan Kettering, New York.

DR. BLAYNEY: Doug Blayney, medical oncologist, Los Angeles.

DR. SLEDGE: George Sledge, Indiana University, medical oncologist.

DR. VANDERPOOL: Harold Vanderpool, University of Texas Medical Branch in
Galveston.

DR. TAYLOR: Sarah Taylor, University of Kansas Medical Center, medical
oncology and palliative care.

DR. FLEMING: Thomas Fleming, University of Washington, Seattle.

DR. ALBAIN: Kathy Albain, Loyola University, Chicago, medical oncology.

DR. CARPENTER: John Carpenter, University of Alabama at Birmingham,
medical oncology.

DR. TIWARI: Jawahar Tiwari, biostatistics, FDA.

DR. CARDINALI: Massimo Cardinali, CBER, oncology.

DR. KEEGAN: Patricia Keegan, Center for Biologics, FDA.

DR. SIEGEL: Jay Siegel, Office of Therapeutics/Biologics, FDA.

DR. TEMPLETON-SOMERS: I\'d like to read the meeting statement of
conflict of interest.

The Food and Drug Administration has prepared general matters waivers
for the following special government employees who are attending
today\'s Oncologic Drugs Advisory Committee meeting to discuss trial
design considerations and appropriate patient populations for studies of
investigational agents for adjuvant therapy of melanoma, given the
availability of an approved agent for this indication.

The meeting is being held by the Center for Drug Evaluation and
Research.

The people with waivers are Stacy Nerenstone, M.D.; Kathy Albain, M.D.;
Douglas Blayney, M.D.; John Carpenter, M.D.; Stephen George, Ph.D.;
David Kelson, M.D.; Donna Przepiorka, M.D.; Jody Pelusi, R.N., Ph.D.;
Bruce Redman, D.O.; George Sledge, M.D.; Sarah Taylor, M.D.; Thomas
Fleming, Ph.D.; Robert Nelson, M.D.

A copy of these waiver statements may be obtained by submitting a
written request to the agency\'s Freedom of Information Office, Room
12A30 of the Parklawn Building.

Because Dr. Otis Brawley, Mr. Kenneth McDonough and Dr. Harold
Vanderpool reported they have no current financial interest in any
pharmaceutical or biologic firm, they do not need a general matters
waiver in order to participate in this morning\'s discussions.

Unlike discussions before a Committee in which a particular product is
discussed, issues of broader applicability, such as the topic of this
morning\'s meeting, may involve many industrial sponsors and academic
institutions.

The Committee members have been screened for the financial interests as
they apply to the general topic at hand because general topics impact on
so many institutions it is not prudent to recite all potential conflicts
of interest as they apply to each member.

FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussion before the Committee,
these potential conflicts are mitigated.

With respect to FDA\'s invited guests, Dr. John Kirkwood has reported
interests that we believe should be made public to allow the
participants to objectively evaluate his comments. Dr. Kirkwood has a
grant from Schering and receives consulting fees from Schering.

Lastly, we would also like to note for the record that George Ohye is
participating in this meeting as an industry representative acting on
behalf of regulated industry. As such, he has not been screened for any
conflicts of interest.

Thank you.

CHAIRPERSON NERENSTONE: Thank you.

Now we\'ll turn to the open public hearing. We have a long list. So I
ask those who are testifying to please stay within the recommended time
frame.

Dr. Spitler.

DR. TEMPLETON-SOMERS: I\'d also like to mention for the record that due
to the wonders of electronics we have been able to receive a lot of
input from the public on this particular issue, mostly in the form of
E-mails. These E-mails are available for your viewing in the desk copies
at the front desk outside.

All of the Committee members and the FDA have received copies of all of
the E-mails that I received as of yesterday. Most of them were shipped
to them last week, and the late ones are in their folders today.

For the most part, the patients in the group are recommending that
treatment options be made and discussed between the patient and their
doctor with freedom for those options, and there are a few other
opinions that you\'ll find in your book.

Thank you.

DR. SPITLER: I am Lynn Spitler. I am the Director of the Northern
California Melanoma Center.

For over 30 years, a major focus of my research activities has been
clinical trials of adjuvant therapy of melanoma, and I have published
extensively on this subject in refereed medical journals.

I personally paid my travel expenses to attend this meeting and
personally paid the cost of preparing this presentation.

I have received research funding from Immunex, Schering and Chiron, am a
consultant to Immunex, and am a member of the Immunex Speakers Bureau.
None of these companies suggested nor contributed to this presentation,
and I have not discussed it with them.

It is the understanding of the melanoma community that the FDA has
instituted a policy that patients with Stage II T4 or Stage III melanoma
who are candidates for therapy with high dose interferon and who refuses
treatment cannot participate in Phase 2 trials of other agents.

We recommend that this policy be altered. Points to consider regarding
this issue are as follows:

High dose interferon may provide clinical benefit as adjuvant therapy in
these patients. However, it is an imperfect solution. The clinical
benefits are limited, and the incidence of severe toxicity is
significant.

Phase 2 trials are needed if the medical community is to develop new
agents with more clinical benefit and less toxicity as adjuvant therapy
for patients with Stage II T4 and Stage III melanoma.

I have presented a written statement for your consideration, and I hope
that has been distributed. The statement provides additional background
regarding the points to consider regarding this issue.

We recommend that patients who choose not to undergo therapy with high
dose interferon, after having been fully informed of the risk-benefit
ratio should be permitted to choose treatment with investigational
agents in approved clinical trials. Such patients should sign consent
form, which clearly states that high dose interferon is the treatment
approved by the FDA for adjuvant therapy of high risk melanoma.

This statement is supported by 37 physicians specializing in the care of
melanoma patients, as evidenced by their signatures accompanying the
statement.

It is also supported by 20 patients who wrote letters of support and
others who wrote letters indicating their support, including Dr. Richard
Shilsky (phonetic), Chair of CALGY; Dr. Robert Dilman, Chair of the
Society of Biological Therapy; Jeff Patterson, co-founder of Melanoma
Patients Information Page; Casey Culbertson, Vice Chairman, Melanoma
Research Foundation; and Professor Alexander Egermont, EORTC Melanoma
Group.

Others have traveled to appear here and make statements personally.

Thank you for your consideration.

CHAIRPERSON NERENSTONE: Thank you.

Dr. Lutzky.

DR. LUTZKY: Morning. My name is Jose Lutzky, and I\'m the Director of
the Melanoma Multi-disciplinary Program at Mt. Sinai Cancer Center in
Miami Beach, Florida.

Our center sees over 200 new melanoma patients a year, and we are
involved in several clinical trials encompassing all stages of melanoma.
I received research funding from Immunex, Celgene, and Chiron
Pharmaceuticals. I\'m a member of the Immunex Speakers Bureau, and I
have conceived this statement individually and without participation or
notification of any pharmaceutical company.

I have paid for this trip from my personal funds.

High dose interferon is considered by the FDA as the standard of care
for patients with Stage IIB3 melanoma. I will not dispute this point
today.

I would like, however, to point out that survival data is of borderline
significance in that 145 months of follow-up, the survival of the
interferon treated group in ECOG 1684 is no longer statistically
different from the observation group.

While life threatening and irreversible toxicity is uncommon with this
treatment, most patients experience prolonged, debilitating side
effects, such as fatigue, anorexia, weight loss, and depression.

In my clinical practice, 60 percent of which consists of patients with
melanoma, I discuss the data on adjuvant high dose interferon with all
patients at high risk for recurrence. About 50 percent of these patients
will proceed to receive the standard of care. The other half will elect
not to be treated with interferon.

In the patients who are actively in the work force, the main reason is
the abundance of side effects, fear of decreased performance at work, or
loss of work.

In the significant proportion of older retired individuals that I see in
Florida, they are not interested in toxic therapy that might interfere
with their quality of life and/or aggravate their existing medical
problems for a borderline survival benefit.

Many older patients cannot self-inject, don\'t have easy access to
transportation, and live alone. These patients could not be monitored
appropriately for high dose interferon treatment.

I submit that there is a need for less toxic, novel adjuvant therapies
for a significant group of patients who are unwilling to receive high
dose interferon adjuvant therapy. These patients end up receiving off
protocol therapy with other agents given by their treating oncologist.

I would like to echo the suggestions of many of my colleagues who treat
melanoma patients and are present here today. Number one, that patients
that choose not to undergo adjuvant treatment with interferon be offered
access to investigational trials exploring novel agents.

Number two, that these patients should sign an informed consent stating
that they understand that treatment with high dose interferon is the
current standard of care, and that in the informed consent, a brief
summary of the results of the pivotal clinical trials with high dose
interferon be included.

Thank you.

CHAIRPERSON NERENSTONE: Thank you.

Ms. Graham.

MS. GRAHAM: Good morning. I\'m Karen Graham, and I\'m the Chair and
President of the William S. Graham Foundation for Melanoma Research.
We\'re widely known as the \"Billy Foundation.\"

I would also like to note that I really appreciate the opportunity to
address you from the advocacy side of this hearing today. Though we have
accepted educational grants from Schering, Chiron, Maxim, and Genta in
the past, I\'ve personally paid my own expenses in order to address you
here today.

In just three days, on March 2nd, I will personally be observing the
eighth anniversary of the passing of our son Billy to this insidious
disease. He died at an all too young age of 22.

When Billy was diagnosed, I made him a promise that we were going to
beat this disease. What I didn\'t realize was that it was not going to
be in his timing, but I still have a promise to keep, and there\'s
nothing more tenacious than a mother\'s promise.

But now, eight years later, it is still not in any melanoma patient\'s
timing, and this is just not acceptable.

In the last eight years, how many new therapies have been approved, and
what is this saying to melanoma patients and their families? We want
patients to have choices from the onset, not as a second matter of
recourse.

In the past eight years, approximately 56,000 lives have died to this
disease, and this is not acceptable.

In the past eight years, approximately 360,000 people have been
diagnosed with this disease. They\'ve had to face it with an extremely
limited offering of treatments available to them. This is no longer
acceptable.

It has been a long time that has passed and that something needs to be
done in order to bring hope to these dear people. I\'m not here to
debate your system of approval, nor am I here to discuss which therapy
is the best. What I\'m here for is to represent those 360,000 people,
many of them who have already died from this disease.

I\'m here to represent the dozens of phone calls that we receive on a
monthly basis from the patients and their families that literally cry
out to us in their battle against this ugly killer.

Choices, that\'s all. They are simply looking for the ability to retain
some semblance of control in a life that has gone totally berserk on
them, and right now as it stands, it\'s not there for them, and this is
not acceptable.

With every phone call, what we hear is, \"Why isn\'t something being
done to allow us more choice of treatments? I want the opportunity to
choose. I want to fight, but I want to have some quality of life in the
process. I just want to be treated like I\'m a person with the ability
to make an informed decision. It\'s my body; it\'s my life. So educate
me. Tell me the pros and the cons of it, of what\'s out there. But then
let me choose.\"

The choices are not acceptable. We\'re standing on the edge of a
research crisis precipice. Researchers are throwing their hands up in
frustration.

I\'ve had the opportunity to speak with many leading researchers from
around the world with more than one of them suggesting to me that
they\'re at the point of leaving, leaving melanoma research.

Distinguished panel, we cannot afford for that to happen. They have
dedicated their entire professional lives trying to create viable
options only to see them literally pulled out from under them at a time
when we as a foundation are doing everything that we can to bring up the
next generation of researchers. We cannot afford to lose the incredible
intellects that are currently in this fight. This is not acceptable.

This, for the most part, is an orphan drug disease, especially for those
more advanced patients. Yet I have not seen any urgency from the FDA in
working with researchers and companies to make potential treatments
available, many of them spending months, if not years, attempting to get
clear direction from the agency on how to proceed with their drug
developments.

To bring help to these patients we must start working together to make
this a common goal. We should be saying what must we be doing together
to make this happen. We must move forward and bring more choices to
patients and show them that we are not only listening, but we are doing.

As a foundation that was brought up on a personal loss, I have been in
those trenches. I have seen the inner workings and had to deal with it
myself and have continued to see how melanoma patients and their
families for the past eight years have had to deal with the same lack of
choices, some of these patients having less than two months to live.

[Ergo]{.underline}, there is principle of risk to benefit, a valuation
that needs to be addressed and applied here. Again, I do not see the
appreciation of this principle and application in working with potential
treatments.

We have knowledge that there are treatments that are considered safe and
potentially effective by clinicians in recent trials. Yet little effort
is being made to accelerate their approval. This can no longer be
acceptable.

I will take it as a rally call to make sure that these patients\' voices
are heard at every opportunity that I can create. I will take it to the
streets. I will take it to conferences and different speaking
engagements that I have around the world. I will take it to state and
national legislators, and I will take it to the press.

I will do whatever I can as the head of this foundation to make sure
that their requests, their requests for the right to choose and to have
options given to them. They\'re tired of being treated like they don\'t
exist.

Inform them. Educate them. Give them the pros and cons of what is going
on. Have them sign a stack of papers a mile high if you must, but then
let them choose. To do otherwise is taking their lives out of their
hands, and I\'m sorry. This is not acceptable.

Thank you.

CHAIRPERSON NERENSTONE: Thank you very much, Ms. Graham.

Dr. Chapman.

(Pause in proceedings.)

DR. CHAPMAN: Thank you.

I would like to applaud the FDA for convening this meeting to allow an
exchange of views on this very important subject.

I\'m head of the Melanoma Section at Memorial Sloan Kettering, and my
laboratory and clinical research has focused on trying to develop
effective immunological treatments for melanoma.

I should state that I have no equity interest in any biotechnology
company or drug company. I\'m not on the speakers bureau of any drug
company.

That being said, I would like to spend my five minutes here explaining
why I and many of my colleagues and patients feel strongly that the
Phase III data do not support the claim that high dose interferon
results in an improved survival and, as such, do not support designating
high dose interferon as the sole standard for adjuvant therapy of
melanoma.

There have been two randomized trials comparing high dose interferon
with observation, E1684 and E1690. These are the only trials capable of
telling us whether high dose interferon is superior to observation
following surgery.

This is the first of my three slides showing the data from E1684 as
originally published in the [Journal of Clinical Oncology]{.underline}
and as updated by investigators from ECOG and presented at several
public meetings.

This was a relatively small trial, only about 140 patients per arm, and
at seven year median follow-up on the left, the interferon group showed
an estimated five year survival improvement of nine percent.

But the question hanging over these data is: is this difference really
statistically significant?

These data were published using a less stringent one sided T test, which
gave a P value of .027. The two sided value is .06, according to the FDA
document which was distributed for this meeting, meaning that the
difference did not reach the standard threshold for statistical
significance.

With the data matured three more years, we get the curves on the right,
and the differences have become even less significant. This is
presumably because more melanoma deaths have occurred in both patient
groups.

The small difference between the groups is not significant, even using a
one sided test, the P value being .09, and the two sided test being .18.

The data from this first trial then leads us to conclude that the
suggestion of overall survival benefit, which was nearly statistically
significant after seven years, is clearly not significant any longer,
and we cannot conclude with any degree of confidence that the overall
survival improved with high dose interferon.

The second trial comparing high dose interferon with observation was
E1690. This was a better powered trial with 202 patients per arm, and
the second slide shows the overall survival from this trial as published
in the [Journal of Clinical Oncology]{.underline}. There was no effect
of interferon on overall survival.

And what I don\'t have time to show is that the effects on relapse free
survival were also note quite statistically significant.

My view is that we have two well conducted, randomized trials comparing
high dose interferon with observation. Neither trial showed a
statistically significant improvement in overall survival, and only the
first smaller trial showed an improvement in relapse free survival.

In my mind, no amount of post hoc analysis can turn or should be allowed
to turn these negative trials into positive ones. This lack of survival
benefit weighs heavily on my view and on my patients\' view of the value
of high dose interferon as an adjuvant treatment.

Patients are willing to undergo a year of fatigue, fever, depression,
diminished quality of life if there\'s an increased chance of survival.
However, in the absence of convincing evidence of any survival benefit,
the interests of patients would be best served by supporting carefully
conducted research on other scientifically valid approaches to adjuvant
therapy.

Patients should be allowed to participate in experimental adjuvant
trials without high dose interferon. Patients should be informed that
high dose interferon is an FDA approved adjuvant treatment, and they
should be told the likely benefits and toxicities.

However, mandating a year of treatment that has been shown in two
carefully conducted and reported randomized trials to yield no
significant survival benefit hinders the development of effective
therapies and is not in the best interest of patient care.

Thank you.

CHAIRPERSON NERENSTONE: Thank you, Dr. Chapman.

Dr. Sharfman.

DR. SHARFMAN: My name is William Sharfman. This morning I speak as a
member of the Johns Hopkins Melanoma Group and as Director of Cutaneous
Oncology at the Hopkins Oncology Center.

I\'m also privileged to serve on the Melanoma Committee of the Eastern
Cooperative Oncology Group, chaired by Dr. Kirkwood, who has taught me a
great deal about the treatment of melanoma and whose work I admire very
much.

Please be aware that I have received honoraria from the Schering
Corporation in 1998, 1999 and 2000 to speak on the subject of melanoma.
As the medical oncologist of our group, much of my time is spent
counseling and treating patients with high risk melanoma. I discuss high
dose interferon with all of them.

I emphasize that as the only treatment shown to be beneficial in Stage
IIB and Stage III melanoma, and it is the only FDA approved therapy.

However, some patients are not fit for high dose interferon because of
other health problems. Many patients refuse interferon no matter how
much time you take to discuss it with them, and some insurances will not
pay for home administration of subcutaneous interferon for 11 months,
leaving the untenable option of a patient visiting the doctor\'s office
three times a week for almost one year.

I also discuss vaccine protocols with all of my patients. I emphasize
that vaccines are promising, but have not yet been proven and are not
FDA approved. We also discuss the option of no therapy.

The patient discussion of treatment options, high dose interferon,
vaccine or observation is very time consuming, but this is what is
required of our patients based on our current level of knowledge.

The decision making process should be between the patient and the
treating physician with the patient and the data in front of them and
not mandated by a third party.

At this point in time, the data on high dose interferon is not so
compelling that patients should be required to get interferon before
they go onto a vaccine trial. In fact, the updated data on ECOG 1684 of
which I am aware shows that there\'s no longer a statistically
significant overall survival advantage for high dose interferon.

The future of adjuvant melanoma therapy is not high dose interferon by
itself. It may be interferon plus another agent. It may be a vaccine, or
it may be some other agent. A requirement to give all Stage IIB and III
patients interferon will seriously slow down our attempts to identify
more active and less toxic melanoma therapies.

At this point, I would like to highlight the conclusion of a letter
written by Dr. Alex Egermont of the EORTC that I believe has been
officially entered into the record of this meeting.

Very briefly, he states that because of inconsistent survival benefit,
toxicity and cost, high dose interferon should not be considered as
mandatory therapy for Stage IIB and III melanoma.

On top of that, patients should keep the right to abstain from therapies
with a toxicity profile associated with high dose interferon and have
options open to them.

Thank you very much.

CHAIRPERSON NERENSTONE: Thank you, Dr. Sharfman.

Dr. O\'Day.

DR. O\'DAY: Thank you.

I\'m Dr. Steven O\'Day, and I\'m a medical oncologist, Director of
Medical Oncology and Medical Oncology Research at the John Wayne Cancer
Institute in Los Angeles.

John Wayne Cancer Institute is one of the larger melanoma referral
centers in the world, and I actively have committed my time over the
last eight years to clinical trials research in a number of different
stages of the disease, including Stage II, III, and IV.

I come here at my own expense. I do have research grants from Chiron,
from Immunex, and from Schering, and I am on the speakers bureau for
Chiron, but I have not discussed any of my testimony today in front of
you with any of these pharmaceutical companies.

I have carefully reviewed the data regarding interferon for Stage IIB
and III disease, and I see approximately six new melanoma patients a
week. Many of these discussions center around IIB and III disease and
the interferon data.

So I am in the trenches. I have these lengthy discussions, and I think
it\'s fair to say that biases aside, the majority of patients that I
discuss this with choose to do high dose interferon therapy. However,
there is a significant minority of patients who, after hearing the date
carefully discussed, choose not to go on therapy.

And we could all agree generally that disesae free survival has been a
consistent finding at least in the dosing schedule that the FDA has
approved. I think overall survival, as some of the previous speakers
have discussed, remains controversial.

But even if we assume best case scenario, and I actually do discuss this
with patients, that there is a small survival advantage, this particular
unique duration of this treatment and the constitutional and
neurocognitive side effects that patients endure leads many of them to
choose not to proceed with this treatment and to forego this treatment.

And I think in that setting, we could agree that high dose interferon is
a standard, but may not be the standard in the sense that our European
and our Australian colleagues, as well as many U.S. physicians and
patients, choose not to follow, quote, unquote, the standard of care.

And it is in this setting that I think it is very important that we
offer patients novel, innovative therapies. And that is what is
critical.

Now, Phase I and II protocols are important to develop new treatments,
and before we assume that we could look at Phase 1 and 2 trials in
either Stage IV disease or in earlier Stage IIA disease, I would want to
remind people that that my not be the best scenario to look at.

We have a unique opportunity because of the surgical staging of this
disease that we\'ve identified a high risk subgroup IIB and III, and
toxicity issues may be better addressed in earlier stage disease, but
preliminary efficacy issues are optimal in a high risk situation of
recurrence with a competent immune system since many of our adjuvant
trials are geared toward immunotherapy.

And I think the Stage IIB and III patients, since they are very high
risk for recurrence and death, and they relatively have an intact immune
system compared to Stage IV disease, is a group that we don\'t want to
lose that advantage to look at Phase 1 and 2 trials and to see some
preliminary efficacy data to take to larger Phase 3 trials.

So I think it\'s for that reason that we have a significant number of
patients that choose not to do interferon, and that this subgroup is an
idea subgroup to look at novel, possibly less toxic therapies, to look
at preliminary efficacy; that it\'s very important that we allow these
patients the freedom of choice to participate in well run, well designed
clinical trials.

Thank you.

CHAIRPERSON NERENSTONE: Thank you, Dr. O\'Day.

Dr. Slingluff.

DR. SLINGLUFF: While he\'s getting that together, I\'m Dr. Craig
Slingluff at the University of Virginia. I\'m the head of the division
of Surgical Oncology, and I run our melanoma program. I\'m also Director
of our Human Immune Therapy Center.

We live in a small town, and most of our referrals come from other
physicians so that most of the patients that we see come to us with an
interest in vaccine trials, having already decided not to take
interferon after informed discussions with their medical oncologists,
although we also insure that we discuss interferon with them as a
separate discussion in any and every case of patients who are eligible.

I should also point out that I have been running several clinical trials
of tumor vaccines, primarily peptide based trials. I\'ve been NIH funded
for most of those trials.

I have also received industry support from Chiron, Immunex,
Schering-Plough Research Institute, and Argonex. I\'m listed as an
inventor on several patents that the university has filed for some of
the peptides that we identified and that we and others use in vaccine
trials.

I am Co-chair of the Melanoma Committee of ECOG and recently appointed
one of the two Vice Chairs f the Melanoma Committee of the American
College of Surgeons\' Oncology Group.

The main question I\'d like to address is how to design Phase 2 trials,
experimental therapies with an FDA approved therapy available, and some
of our recent exposure to this issue has arisen with this particular
trial, which we call UVA-Mell39, which is a peptide based vaccine trial
where eligibility includes patients with Stage IIB and III disease
that\'s resected. We\'ve initially proposed the trial to include
patients who refuse interferon or are not candidates for interferon.

The FDA ruling was that patients who are not candidates for interferon
can enter the trial, but for those who simply refuse interferon, they
are not considered candidates.

It was pointed out, however, by our product reviewer that those who have
refused interferon and have not taken interferon for six months or more
after they have definitive surgery are no longer considered candidates
for interferon because of the lack of evidence for efficacy at that time
point, and that they then become candidates for the trial, which
presents an awkward situations where we can discuss with patients who
come to us who are interested in the vaccine trial and have decided not
to take interferon that they cannot enter the trial now, but if they
wait six months, then we can reconsider them.

Obviously we can\'t make a commitment. Now, we have had a number of
patients who have waited six months and have come in. We have had the
also awkward situation arise where one patient so far has waited six
months, came in at the end of the trial as a candidate in all respects,
except that he had a local recurrence at his site of his primary tumor,
which makes apt Stage III disease and a candidate for interferon again.
So we tell him he has to wait another six months for entry into the
trial.

The argument for legislating against the freedom of patients to decide
to enter a clinical trial after refusal of an approved therapy is that
patients may be exposed to risk of obtaining inadequate information
about the standard therapy, which may be affected by real or intention
or unintentional bias of clinical investigators.

However, the process of informed consent is one on which our entire
process of clinical research is based. It is what we believe is capable
of allowing patients to make informed decisions consenting to clinical
studies where there may be unknown benefit and known or unknown risks.

To argue that informed consent cannot provide adequate protection of
patients who choose not to take an approved therapy where they can have
explanations of the risks and benefits of doing that is tantamount to
arguing that informed consent cannot provide adequate protection of
patients in any setting, and this argument then threatens the whole
basis of our clinical trial program in the United States.

A tenable policy for the design of Phase 2 clinical trials in patients
who may be eligible for an FDA approved therapy should assure a patient
protection while also assuring the freedom of self-determination by
patients. My suggestion is that for trials where patients may be
eligible or ineligible for the standard therapy, they should reach
documentation on the consent form of whether they\'re eligible or not
for the standard therapy.

If they are eligible for that, then they should have to review a
standard packet of information that would be FDA approved as part of the
clinical trial program, which would require them not only to read that
information, but also to sign off on individual points that are
considered key, if interferon is approved, the survival advantage, et
cetera. Several of those could be listed.

The benefits of this is one is that it would insure that no patient
eligible for an FDA approved therapy would refuse that therapy and enter
a trial without receiving acceptable information about the standard
therapy, but it also would lead to more uniform information
dissemination about the standard therapy than currently provided to
those who refuse that therapy.

Many patients now see a medical oncologist who may or may not \-- who
may not feel that interferon is the best thing for them and tell them
not to take it. I have patients who come seem me to tell me their
medical oncologist said not to take interferon.

Those patients who choose not to take interferon based on that
recommendation go home and don\'t take it. If, instead, they are
referred to be considered for entering into a clinical trial where
they\'re forced to review all of the data, then have an opportunity to
see all of the data and then make a decision to take interferon or some
other standard therapy in a different setting.

This would also permit patients freedom to choose the management they
find most consistent with their priorities and ultimately would actually
increase the proportion of patients whose therapy is regulated and
monitored by the FDA, thereby improving patient safety generally.

I believe very strongly in the recommendation I\'ve made, which is
consistent with many you\'ve heard, and also the recommendation if the
FDA does not feel comfortable making that decision at this point would
be that since interferon has been tested within 56 days of definitive
surgical therapy, and now some patients are being entered into trials up
to about three months, but there\'s really no convincing data about its
benefit after three months, its interferon use after three months can be
considered experimental.

So it would be appealing if the regulation requiring a six month delay
before entry into clinical trials could be shortened to three months.

And that\'s all. Thank you.

CHAIRPERSON NERENSTONE: Thank you, Dr. Slingluff.

Dr. Schuchter.

DR. SCHUCHTER: Good morning. My name is Dr. Lynn Schuchter, and I\'m a
medical oncologist at the University of Pennsylvania Cancer Center.

I treat patients with melanoma, with early and advanced disease. I
appreciate the opportunity of speaking before you today.

I\'ll state that I have no conflict of interest. I\'m not in any
speakers bureaus. Our institution does conduct ECOG trials and we do
participate in a number of vaccine clinical trials.

The optimal care for patients in the year 2002 for patients with
melanoma, I think, is now clear. While interferon is appropriate for
some patients, it is not the standard of care. It has not been adopted
as a standard of care by many physicians in the medical community, nor
by patients, and the reason for this is really twofold.

One is the issue of efficacy, and the question of whether interferon is
associated with improvement in overall survival.

And the second issue is the considerable toxicity associated with the
treatment.

I think previous speakers have really outlined the survival issue, but I
would just add one more point about 1684, which is really the main trial
that we focus on in terms of this question of survival benefit.

In that study most of the patients had node positive disease, and at the
time that the study was initiated, it was unclear that the most
important predictor of relapse is the number of lymph nodes involves,
and that study did not stratify patients for the number of positive
nodes.

I can\'t imagine doing a node positive breast cancer trial without
knowing and stratifying appropriately for number of positive nodes.

So while it\'s stated that the two arms are appropriately balanced, it
may not be balanced in an important way which also could affect the
overall results.

A second issue is the toxicity issue. In 1684, three quarters of the
patients had dose reductions for Grade 3 or 4 toxicity. I know of no
other adjuvant therapy that is associated with such a high incidence of
serious toxicity, Grade 3 and 4 toxicity.

I think this debate would be much less heated with this efficacy data if
the toxicity associated with the treatment was not so substantial.

Fifty percent of my practice is also patients with breast cancer, and I
administer a lot of adjuvant therapy in the breast cancer setting. I
think there is on comparison regarding the toxicity of one year of high
dose therapy of interferon, even with dose reductions and comparing that
to three or six months of adjuvant chemotherapy for patients with breast
cancer.

I think there is an analogous situation in patients with Stage II colon
cancer where there\'s a lot of debate about the efficacy of adjuvant
therapy. In a number of studies the benefits of adjuvant therapy for
survival ranges in about three to eight percent in the adjuvant setting
for Stage II colon cancer patients.

Yet right now currently the cooperative groups are offering a side range
of options for those patients. The CELGB has a study of surgery versus
antibody, and in patients participating in NSABP studies, the options
are 5 FU leucovorin chemotherapy versus 5 FU leucovorin oxaliplatin.

So in a similar situation, patients are offered really a wide range of
options after, again, getting full informed consent about the potential
benefits of adjuvant therapy.

I urge the FDA to alter its policy regarding the testing of new agents
in patients with melanoma. The majority of patients with Stage III
melanoma die from melanoma despite high dose interferon. We clearly need
better therapies for these patients.

It is not the standard of care to use high dose interferon. It has not
been accepted by the medical community, nor patients, and I believe that
the current FDA policy is a significant obstacle to our finding better
therapies for our patients and therapies that are better tolerated.

Thank you.

CHAIRPERSON NERENSTONE: Thank you, Dr. Schuchter.

Dr. Li.

DR. LI: Good morning. My name is Dr. Vincent Li, Scientific Director of
the NGO Genesis Foundation, a global, nonprofit organization dedicated
to advancing the field of molecular targeted therapies for cancer and
other diseases.

Interferon alpha IIB was approved in 1997 for the treatment of node
positive or deep Stage IIB melanoma. Since then a number of
investigational biological agents have been studied as adjuvant therapy,
including Melacine, in allogeneic cell vaccine derived from two melanoma
cell lines.

A Phase 3 melanoma trial of Melacine as monotherapy using observational
controls showed no statistical benefit for overall disease free
survival, but benefit was seen for a subset of patients with Class I
MHC, HLA A2 or C3 markers.

A major issue is how to design pivotal clinical trials for this patient
group, given the availability of an approved beneficial drug such as
interferon. This type of question is not unique to this agent, nor to
this tumor type, but in fact, faces a larger number of other novel
molecular targeted therapies in development for cancer.

The NGO Genesis Foundation is studying the design of clinical trials for
molecular targeting agents that affect tumor blood supply. Melanoma is a
highly angiogenic tumor where increased vascularity correlates with
invasion, metastases, and poor survival.

Certain melanoma treatments, including interferon alpha, possess
anti-angiogenic activity, and their anti-tumor effects are attributable
in part to anti-angiogenesis.

Interferon alpha is a complex agent possessing divers and sometimes
adverse immunomodulatory effects in patients. Therefore, melanoma trials
testing new agents in combination with interferon need to be examined in
the context of two issues.

First, the possibility for enhanced efficacy, and second, the
possibility for enhanced toxicity.

On the one hand, combinatorial therapies involving interferon with a
vaccine may have synergistic effects resulting from combining
anti-angiogenic with immunomodulatory actions.

In the field of anti-angiogenic therapy, it is now strongly believed
that combinatorial regimens involving a novel agent with the best
available standard therapy will generate the most potent anti-tumor
response.

In the case of a melanoma vaccine, interferon induces monocytes to
differentiate into dendritic cells, and this might enhance immunity
against the tumor. Interferon\'s anti-angiogenic activity might suppress
melanoma growth by decreasing the production of stimulatory molecules,
such as basic FGF, VEGF, and Interleukin-8 by inhibiting matrix
Metaliprotenase-9 and by inducing endothelial cell apotheosis.

Together, a melanoma vaccine plus interferon might generate a more
efficacious response.

On the other hand, a combinatorial approach obscures the full evaluation
of both safety and efficacy of the new agent itself. Toxicities in a
combination cannot be easily separated, and some toxicities may be
additive or cumulative in nature.

Another concern is whether the well known toxicities of interferon might
negatively impact a vaccine trial. For example, in a recent trial of a
ganglioside based melanoma vaccine, one third of patients receiving a
high dose interferon stopped treatment during induction due to
interferon toxicity, and 50 percent stopped or had their interferon
doses held during maintenance therapy.

High dose interferon has been shown to have significant clinical
benefit, while low does use remains unproven.

Attrition of patients due to dose related interferon toxicities may
weaken an efficacy study by closing completion of accrual and possibly
by selecting out subgroups of patients who share susceptibility to
interferon\'s effects.

Because of such toxicity concerns, it may be prudent to learn how a
novel melanoma vaccine performs along when directly compared to
interferon, and such comparisons should, of course, be studied
prospectively and not historically inferred.

For vaccine trials of melanoma, we recommend that the FDA consider a
three arm trial design, one arm, where the experimental agent is
combined with interferon; a second arm giving interferon alone; and a
third arm with the agent alone.

Such a design accommodates the study of synergistic drug effects both in
terms of efficacy and safety, and this approach may also ultimately
identify a drug that is superior to interferon, advancing the frontiers
of melanoma management.

Thank you.

CHAIRPERSON NERENSTONE: Thank you very much, Dr. Li.

Dr. Rosenberg.

DR. ROSENBERG: Good morning. I\'m Dr. Steve Rosenberg. I\'m a surgeon at
the National Cancer Institute.

The only conflict that I have in preparing these remarks is to somehow
stay on the good side of the Food and Drug Administration because I
almost daily depend on their approval for studies that I do, but at the
same time, to talk about how inappropriate I believe the current policy
is.

In any democratic society, in any good clinical situation, the doctor
and the patient will sit together to discuss the possible benefits and
risks of any treatment offered for that particular patient.

And when a treatment does have some possible benefits, but also some
toxicities, the doctor and the patient sit together to talk about the
impact of the toxicities on that patient\'s life, and we do that every
day; talk about the possible benefits, and then the doctor and patient
together make a decision about whether the possible benefits are worth
the possible risks.

Now, it\'s very rare that we mandate a treatment even when it\'s known
to be effective if it has toxicities, and perhaps the best example that
I face almost every day is in the administration of high dose
Interleukin-2 to patients with metastatic renal cell cancer and
metastatic melanoma. To my knowledge, high dose Interleukin-2 is the
only approved treatment by the FDA for patients with metastatic kidney
cancer.

And in fact, in our trials of many hundreds of patients and other
published trials about eight to ten percent of patients with widely
metastatic cancer will have a complete regression of all of their
disease. Eighty percent of those will never recur, and we have many
patients beyond ten years cured of widespread kidney cancer, and that\'s
true for melanoma as well.

There is one other approved treatment: Dacarbazine. And yet we don\'t
insist that every patient who has metastatic kidney cancer receive high
dose Interleukin-2. It has toxicity associated with it, and patients can
decide whether or not that eight percent chance of a durable, complete
response is worth the toxicity that they may receive due to
Interleukin-2, and in fact, those patients are certainly eligible to
enter highly experimental Phase 1 trials that have no benefit, and we
leave that decision to that patient.

And I believe that that is appropriate, even though I do feel that high
dose Interleukin-2 can benefit many patients.

Now, with respect to the situation with alpha interferon and the
adjuvant setting that we\'re discussing today, I think there are two
compelling points, and they\'ve been made already. I\'ll just reiterate
them very briefly.

The first is that the data that alpha interferon is beneficial in
patients in the adjuvant setting is controversial. There are some data
that it is of benefit, but you\'ve heard from Dr. Chapman an elegant
analysis showing that it is of no survival benefit.

And in fact, the literature that I try to keep very closely in touch
with and analyze tells me as I analyze that data that alpha interferon
does not have a survival benefit, and as a physician treating many
patients with melanoma, that\'s a judgment that I make. Other physicians
might make other judgments, but it is a controversial issue.

And in fact, the leaders of ASCO, the Society of Biologic Therapy, the
EORTC, and other groups feel similarly and, in fact, they\'ve submitted
letters, many of them, saying that, in fact, they do not either believe
that alpha interferon is beneficial.

And so there is controversy about its benefit. There\'s no controversy
about its toxicity. It has caused deaths in the adjuvant setting in
patients who might have been cured in the absence of its administration.

Many patients who take interferon and then recur and come to us for
other treatment will tell me that it was worst year of their life. They
were tired the entire year. They find even high dose Interleukin-2 much
more palatable than a year of this interferon.

This is certainly a toxic treatment, and personally if I had melanoma in
the Stage III setting, I would not take alpha interferon because I do
not believe the possibility of benefit is worth the toxicities that one
would experience, and I find it therefore hard to understand why the FDA
would mandate that as the only possible treatment.

The second point, in addition to the controversy as to the value of
interferon is the fact that in any democratic society, a patient and a
doctor should have the right to sit down, look at the data, and together
decide whether or not a treatment of marginal benefit or even definite
benefit is worth the toxicities and be allowed to decide not to take
that treatment and, instead, take a fully informed other experimental
treatment that might be beneficial to them.

And, in fact, the current regulation that insists that a patient must be
refractory or recur after alpha interferon before they\'ll accept other
experimental treatments has to me the somewhat insulting implication
that, one, the doctor is not going to tell the patient all of the data
about alpha interferon honestly, plus and minus, and the other rather
insulting implication that the patient is not adequate to decide once
they\'re fully informed.

And I believe that the basis of both of these points, the current policy
is an unreasonable one and, in fact, an intrusion into the
doctor-patient relationship.

The majority of patients today whether they receive alpha interferon or
not, who have multiple positive lymph nodes from melanoma, will die of
melanoma. We desperately need better treatments, and I think the current
policy of insisting that patients receive alpha interferon, that does
not allow us to explore the application of exciting, new developments is
actually doing a great disservice to the research community and, in
fact, stifling research that could potentially lead to more effective
treatments.

Thank you.

CHAIRPERSON NERENSTONE: Thank you, Dr. Rosenberg.

We are a little bit ahead of schedule, but I\'d like to continue on.
Next is the FDA presentation by the Center of Biologics Evaluation and
Research.

(Pause in proceedings.)

DR. CARDINALI: Dr. Nerenstone, members of the Committee, ladies and
gentlemen, good morning. My name is Massimo Cardinali. I\'m a medical
reviewer with CBER, and I\'m going to introduce the CBER presentation
this morning and cover the first segment of it.

This morning we want to present you with some background data on the
experience that CBER has with product studied for the treatment of
melanoma, and also over the basis for approval of INTRON-A for the
adjuvant treatment of melanoma.

Then we will have a survey of the literature of randomized controlled
trials of alpha interferons in melanoma, and give some information on
the comparison of the effect size of other adjuvant treatment for
oncologic disease.

We also have two invited speakers Dr. John Kirkwood will give us an
update on the ECOG experience of the four trials that they have
conducted, and Dr. Joseph Ibrahim will talk about models for adjuvant
trial design.

As regulatory consideration, FDA has placed a clinical investigation on
hold if a patient can be exposed to a reasonable, significant risk of
injury, and this applies to withdrawal of an effective treatment for
that disease.

So the evolution of the regulatory approach in subject with State IIB
and III disease has changed over the years because the initial result of
1684 and 1690 did not show a clear effect on survival, but with the
result of Study 1694 and other published literature, the evidence of
effect on survival was somehow strengthened, and therefore, it was
decided to restrict the enrollment of this subject to those patients who
were medically unable to tolerate the approved dose and schedule of
INTRON-A to a subject who had a lapsed time from surgery of more than
six months or to patients who had a recurrence on INTRON-A treatment or
had completed INTRON-A treatment.

Let me give now some information as a background of the last 25 year
experience in biological treatment for melanoma. We searched our
database between the year 1975 and 2000 for cancer treatment INDs
submitted to the agency, and of these 26 hundred applications, 196 were
for the treatment of melanoma.

We retrieved from our archives the annual report for a large majority of
this IND and evaluate the number of subjects that were included in the
study and the type of study.

And also we are going to present some data on product category.

As you can see in this five year intervals, the increase in the study
for the treatment of melanoma has been quite dramatically particularly
in the last five years, and here I have some figures for patients
included in different phases of study and divided by number of study and
number of subjects.

The investigational products that were studied are presented here. Tumor
vaccine gene transfer product, monoclonal antibody, cytokines, and this
could include other therapeutic protein, and cellular therapies where we
include LAC (phonetic) cell and tumor infiltrating lymphocyte.

The relative frequency of this product is shown here with vaccine having
the lion\'s share with more than 50 percent of the applications received
by CBER.

And a few more words about tumor vaccine. Again, in order of frequency,
the larger group is tumor cell vaccine is a heterogeneous group of
product. It\'s represented by an autologous cell or allogeneic tumor
line either modified or modified by chemical or gene transfer method.

We also have peptide vaccine, antigen presented by the dendritic cell
and tumor cell lysates or fragments.

And now briefly some information about the basis for approval of
INTRON-A and supplemental data that the FDA reviewed which is reflected
in the current label for INTRON-A. The pivotal study is ECO 1684. The
data for this study was submitted to the agency in 1995, and the
analysis of the agency discussed at the ODAC Committee, and the
committee voted for approval of this agent, and the approval was granted
the same year.

The structure of the study is shown in this schema here. All patients
underwent surgical excision followed by regional dissection for
pathological staging of the disease, and then patients were randomized
to high dose and had no treatment.

And here are the results in the analysis of the FDA with the highly
significant P value for the relapse free survival and clearly
significant P value for the overall survival.

These are the Kaplan-Meiers that were presented in the published report
for the disease free survival, and the Kaplan-Meiers for the overall
survival.

The label indication reads as follows: interferon is indicated for
patients with high risk for systemic recurrence within 56 days of
surgery, and this refers to Stage IIB and III subjects.

At the time that 1684 was presented at the Advisory Committee, Study
1690 was already ongoing, and the two major difference between these two
studies that the pathological staging was not required for all patients,
and a low dose arm was added to the high dose arm, where interferon was
administered for a period of two years.

Here I\'ve presented again the Kaplan-Meier estimate presented in the
published report, and you see that for relapse free survival, there is
separation of the two interferon arms compared to treatment, where for
the overall survival of the curve are much closer.

And in this table, we summarize the data at three years, at the time
point of three years for the high dose portion of 1690 compared with
1684. That, again, showed the effect on overall survival was not
confirmed, although the data is still leaning on the side of the data
presented by 1684.

All of this data was incorporated in the current label for INTRON-A.

The adverse event of treatment with alpha interferon are schematically
\-- very briefly, the non-serious adverse events are common, but
conversely, serious adverse events represent less than two percent, and
both non-serious and serious adverse events are reversible with dose
modification and medical management.

The serious adverse event observed in the clinical trial are liver
failure and depression with suicidal ideation. Two patients died of
liver failure in Study 1684. This is believed to a reactivation of
latent hepatitis condition, and with careful screening, this event is
not observed in subsequent studies.

Also, retinopathy has been reported from post-marketing surveillance to
occur not in patients actually with melanoma, but with other disease.

And finally, I want to present some data on the use of INTRON-A that was
provided to the agency by Schering-Plough. These are data derived from
the sale survey and should be taken with a limitation of the method to
obtain this data.

But it tells us that roughly 60 percent of the subjects with Stage III
disease are treated with INTRON-A, and 20 percent of the patients with
Stage IIB are treated with INTRON-A.

One thing that should be noted is that there is a possibility that some
patients will also be treated with Roferon off label does increase
slightly this value.

And now I will turn the podium to Dr. Tiwari if there are no questions.

DR. TIWARI: I\'m going to present a survey of the published literature
on melanoma and interferon treatment, and this survey is essentially the
same that was presented at this Committee meeting in September of 1999.

Since that time we have one major published study by Dr. Kirkwood, ECOC
1694, and the two trials that were published in abstract form were
published in full reports, and last year a meta analysis of all
published trials were published by Wheatly from England. We\'ll come to
that result a little bit later.

In the survey, we have included only the randomized trials. The
randomized trials that have used observational concurrent controls where
interferon was used as adjuvant treatment.

And just as usual, we went to various databases and searched all of the
published material with the help of the FDA library staff. We had some
individual patient data in our IND files, and we used those data to get
the estimate of the odds ratio and statistical significance and 95
percent confidence intervals.

We have used the summary data from published reports. We couldn\'t get
the individual patient data from all investigators.

We did contact some of the investigators to get the additional
information so we could get a better handle on the odds ratio and the
statistical significance.

The estimates of the odds ratio were obtained using Peto\'s (phonetic)
observed minus expected methods. We used the number of observed events
and the number of expected events to get the estimates of the odds
ratio, the 95 percent confidence interval, and the associated P values.

We also tried to get some estimate of the survival, the relapse free
survival and overall survival at a fixed point at three years.

In the published studies, we had nine trials that were published using
interferon as the adjuvant treatment in melanoma, and out of these nine
trials, Dr. Kirkwood\'s Study 1684, 1690, and 1694, they have used high
dose of interferon.

Dr. Cardinali has already showed you the primary results from Study 1684
and 1690, and here at the results. These are the published results from
the Study 1694 in which interferon was compared with GMK vaccine.

The point here I want to show with respect to the disease free survival
and overall survival, the outcome in the interferon arm is better than
the vaccine arm.

There were two studies in the literature that have used low dose of
interferon. One is study from Italy\'s Rusciani, [et al]{.underline},
and the Scottish Melanoma Group published by Cameron, [et
al]{.underline}., have used the low dose INTRON-A.

The study by Rusciani, [et al]{.underline}., did not give any
Kaplan-Meier estimate of the overall survival or relapse free survival.
They just gave recurrence rate at three years, and in this history, the
control arm at 30 percent recurrence rate as compared with only 13
percent in interferon arm. So here, again, with respect to recurrence
rate, interferon shows better outcome.

And the difference of this 17 percent was significant.

And here are the results from the Scottish Melanoma Group where low dose
INTRON-A was used. This is relatively small study, but here again, the
interferon arm, the outcome in the interferon arm is somewhat better
than the control arm.

Then we have four studies in which Roferon was used. The study by
Creagan, [et al]{.underline}., used high dose of interferon, and the
three other studies, Cascinelli does a WHO trial, and Grob did the
French trial, and Pehamberger the Austrian trial. The last three studies
have used low doses of Roferon-A.

And here are the results from the Creagan trial. Again, just like
before, the interferon arm is somewhat better than the control arm with
respect to the disease free survival and the overall survival.

This is the result from Cascinelli, [et al]{.underline}, the WHO trial,
in which low dose interferon was used. The results of the no treatment
and interferon arms are very close, but here again, the interferon arm
is just slightly better than the control arm.

This is the results from the French study, Grob, [et al]{.underline}.
Interferon again just like what we saw before. The interferon is just
somewhat better than the control arm with respect to the disease free
survival and overall survival.

And finally, we have the data from the Pehamberger study, the Austrian
melanoma group trial. They give only results for the disease free
survival. There is no result with respect to the overall survival in
this trial, and here again, the interferon arm is better than the
control arm.

So using the data from all these nine studies, we got the estimate of
the odds ratio, the 95 percent confidence interval associated with this
odds ratio, and we tried to get some estimates of the odds ratio based
on all of the data that\'s available in this literature survey.

In this graph, the small vertical line is the point which indicates the
estimate of the axis for that particular study. The horizontal line
around that small vertical line is the width of the 95 percent
confidence interval.

The blue line at one is the reference point when, if the interferon arm
and the observation arms were showing identical results. Then the odds
ratio would be equal to one.

And if odds ratio is less than one, then the interferon arm is doing
better than the control arm. If the odds ratio is more than one, then
the interferon arm is doing worse than the control arm.

So here in the case of the relapse free survival, all odds ratios are
less than one. They\'re very consistent. They\'re all less than one.
However, five of these studies, the 95 percent confidence interval
processes the reference line of one showing that there is no significant
difference between the treatment and control, and we saw some of these
were very, very close.

The overall estimate of the odds ratio based on 3,536 patients all
together is here at the bottom in the color bar and that estimate is .8,
which is highly significant with a P value of .0001. So with respect to
the relapse free survival, we have 20 percent reduction in relapse rate
based on all the data from these nine studies, and that\'s highly
significant.

With respect to the overall survival, the trend is similar. All
estimates of the odds ratio for overall survival is less than one, some
of them just slightly below one; some of them a little bit better than
that.

But here in comparison with the relapse free survival, there is only one
study, Dr. Kirkwood\'s. I think it is the 1694 trial where the
difference between the treatment and control is significant. Other
studies, individually they do not show significant difference between
the treatment arm and the control arm.

The overall estimate of the odds ratio is about .9, and that line, the
upper limit of the 95 percent confidence interval crosses the line of
one with a P value of .065. So it is of borderline significance, not
significant at 5 percent. The P value is .065.

Finally, we saw a published report. It\'s in an abstract form in last
year\'s ASCO report, a meta analysis published by Wheatley. This is a
British group. They have looked at essentially the same database that we
have looked at with the two differences. They have used data from two
EORTC trials and one British trial.

They say that they have used only the published reports with the
exception that the two EORTC trials and one British trial, they have
used the individual patient data.

These three trials have not been published, and we do not have access to
these data. Therefore, we have not used in our combined analysis.

However, this group has not used Dr. Kirkwood\'s 1694 trial in their
combined analysis, and they have approximately 3,700 patients. We have a
little bit less than that, about 150 or so less than that.

The results published in this abstract is very similar to our results.
Those two estimates of the odds ratio for the disease free survival are
almost identical. The estimates of the odds ratio for the overall
survival are almost identical, and that\'s not surprising. We are
essentially looking at the same database, and we came up with the same
result.

But the point that I want to argue is the two independent groups of
people have looked at the same data, and they have pretty much the same
conclusion.

Then we also looked at the effect of interferon at a fixed time point,
at three years, and if you pull all of the data together from these
studies, it shows about eight to nine percent absolute improvement in
relapse free survival at three years, and about half of that, four to
five percent absolute improvement in overall survival at three years.

So, in summary then, based on all of the published studies, we have
clinically important and convincing evidence of reduction in relapse.
It\'s about 20 percent reduction in relapse rate, and the P value is
highly significant, that is, less than .0001.

We have some evidence of improvement in survival. Again, the totality of
the evidence shows that about ten percent of the reduction in death
rate, and this P value is about .065 in our analysis, and the British
group says it\'s .05, exactly .05, but they have about 150 or so more
patients in data. So the difference could be because of the additional
patients that they have in their analysis.

And finally, in the last slide, we have listed some effects size in
other adjuvant treatment. We have seen in melanoma we have 20 percent
reduction of the recurrence rate. In 5 FU/Levamisole in colon cancer the
effect size is about 38 percent, but for Taxol and Tamoxifen it\'s very
similar to interferon, about 22 percent.

With respect to the death rate, we saw in the interferon our estimate of
about ten percent. It\'s about 35 percent for 5 FU/Levamisole in colon
cancer, 26 percent for Taxol in breast cancer, and 18 percent for
Tamoxifen in breast cancer.

So the effect size of interferon is somewhat similar to the effect size
of the other adjuvant, especially in breast cancer with respect to the
recurrence rate, but is much smaller with respect to the overall
survival as compared to the Taxol, Tamoxifen and Levamisole.

Thank you.

CHAIRPERSON NERENSTONE: Next on our agenda, Dr. Kirkwood is going to
discuss the efficacy and safety of high dose interferon, the ECOG and
intergroup trials.

DR. KIRKWOOD: Members of ODAC and esteemed colleagues, it\'s a pleasure
to return to present these data to you, having been here in 1995 for
1684, in 1999 for 1690, and now with perhaps the chance to review the
aggregate of our experience to date.

So I will lead off, and then after my presentation \-- and I should say
I\'m John Kirkwood from the University of Pittsburgh \-- Joe Ibrahim,
statistician for the ECOG for the last eight years, will present
statistical design issues that have been our consideration for the
1690-1694 intergroup trials, and for a host of subsequent trials which
we have been designing and undertaking, as he will show you.

The rationale for the inclusion of Stage IIB and Stage III patients into
our trials of adjuvant therapy is illustrated here where for Stage III
the relapse free and overall survival is very short. As you know, the
survival for these patients, a median of three years or less on the
basis of the AJCC data that was as the trial 1684 and 1690 were
designed.

According to the more recent AJCC 2002 formulation, the risks are much
more precisely defined for subsets of patients, and what I\'ve
illustrated here in white are the groups of patients who would have been
those entered into the three trials we\'ll talk about.

I should note for you that we have now T3b, that is to say ulcerated
intermediate depth tumors, which have a very similar prognosis to
several of the groups that were entered into these trials, and that in
overview those patients who have either deep primary tumors or who have
microscopic regional lymph node disease have a greater than 30 percent
mortality at five years from this disease; that those patients who have
macroscopic or palpable node disease, and certainly those with recurrent
nodal disease that were included as half of the trials we have talked
about, have a 60 percent mortality at five years or greater, and so the
risk for these patients is certainly not low.

Sentinel node mapping has come of age in the interval. We have conducted
these trials, and this is data from Jeffrey Gershenwald showing you that
for patients who have been identified to have microscopic regional nodal
disease, the 36 month relapse \-- and here it\'s plotted in the orange
line \-- is about 50 percent, and so microscopic nodal disease in
Gershenwald\'s summary studies is certainly also an ominous feature.

So the entry criteria for the studies we\'ll talk about, for the first
two studies, E1684 and 1690, observation controlled trials conducted
1984 through 1995 in terms of the design. We had treatment versus
observation.

After the approval of this, the first trial that was initiated after the
approval of high dose interferon, we tested a promising vaccine against
high dose interferon.

The entry criteria broken out for these trials is summarized here. Stage
IIB disesae, where either the patients were established as an E1684; the
were all established to be free of disease by elective node dissection
or, in subsequent trials where from five to 20 percent of patients had
selective node dissection or elected no dissection.

In 1690 and 1694, as has already been mentioned, clinically node
negative patients were allowed to enter, but far and away the largest
groups of patients had nodal disease, either presenting lymph node
disease, Stage III disease in both the old and the new system, or
regional nodal recurrence, as I\'ll come back to discuss, is one of the
most ominous prognostic factors that we have to deal with.

Summarizing the demographics of patients in the three trials we\'ll talk
about, 1684, 1690, and 1694, we see a rise in the number of patients who
had node negative disease, from 11 percent in 1684 to a quarter of the
patients in 1690 and 1694.

By converse, the proportion with recurrent nodal disease fell from two
thirds of the highest fraction in 1684 to half in 1690 and a third in
1694.

The E1684 design, as has already been discussed, involved observation
control induction with four weeks of intravenous daily therapy with 20
million units per meter squared per day, five days a week for four
weeks, followed by maintenance therapy at ten million units per meter
squared thrice weekly for 48 weeks.

As Dr. Ibrahim will discuss more, this design was an exponential model.
We did not know the cure rate data that was the basis for cure rate
models in subsequent trials, and stratification used AJCC
stratifications that were then currently available, although
subsequently we have analyzed this trial for numbers of nodes involved,
and there is good balance.

The results of the 1684 study show that median relapse free survival was
improved, as has already been mentioned. P1 value, the one sided P test
as designed in the trial, .002. The overall survival improved, again,
one sided test, .023. And the estimate of five year relapse free
survival rose from 26 percent to 37 percent. The estimated five year
overall survival from 37 to 46 percent.

This is the graphic that you\'ve seen now to many times. High dose
interferon with after four years an apparent plateau in the relapse rate
of patients who were treated. Observation in blue. The prolongation of
median interval to relapse from one year in 1684 observation arm to 1.72
years, for a nine months\' gain, from this treatment.

The overall survival as published at seven years of follow-up, again, an
apparent plateau beginning after five to six years and a rise from 2.78
years\' median survival in the observed population to 3.8 years in the
treated population.

The conclusions we drew from this study, that both relapse free and
overall survival are significantly prolonged with high dose interferon;
that after surgery alone, half of patients in the observation arm
relapsed. So, again, not a favorable group, even though that has been
said otherwise.

High dose interferon was proved on the basis of testimony in July of
1995, and basically to stack this up against the available other
therapies, the 11 percent relapse free survival, nine percent overall
survival gain compare well with the NSABP-93 publication for FU
leucovorin, nine and seven percent, for rectal carcinoma as you see
here, and for breast cancer, nine percent for both relapse and survival.

So 1690 was designed already at the time that these data became
available. It was already accruing. This trial was an attempt to define
where the low doses of interferon might have similar benefit to the high
dose interferon that was seen already in 1684.

The goal now by cure rate model, as Dr. Ibrahim will discuss in detail,
to analyze this impact and to stratify both by numbers of nodes involved
and by the old AJCC stage groupings.

The benefit now expressed in terms of hazard ratios with observation
compared to treatment show that for high dose interferon the hazard of
relapse is 1.28 times greater for the observed patients than those who
receive the interferon; low dose interferon, 1.19.

This approached marginal significance. This, of course, is not, and
there was no survival benefit, as you see with hazard ratios, one for
both survival impacts.

The graphic that you\'ve seen already for high dose interferon, a
benefit compared to observation that was significant, .05; for survival,
obviously no difference in this trial.

So we looked at this trial, and we asked what could have been the
difference, and this is a graphic display in histogram fashion with
observation groups in blue, treatment groups of high dose interferon in
yellow. The period of time up until relapse in the darker portion of the
bars.

And what one sees is that in observation of 1684 versus treatment in
1684, we gained nine months in relapse free survival. In comparison, in
1690 we gained ten months in relapse free survival, but the anomalous
feature in this histogram presentation is the post relapse survival of
the patients entered into the observation arm in 1690.

So the question became what could this be due to, and the answer,
apparent because we had already testified and we already had the
approval of this, is the patients had access to interferon in the 1690
observation arm, and when we looked at these patients who had failed
observation with regional resectable nodal disease, we discovered that
in every single case but one resection had been done and treatment after
the fact, crossover to interferon had been given.

And so unplanned, because at the time that this study was designed we
didn\'t know 1684 would be proved, we have asymmetrical crossover that
may have provided the explanation for some of these differences.

The overall survival plots have taught us some other things. For 1684 in
the dark blue, 1690 in the light blue, the evidence that we need
prospective, randomized Phase III studies to draw any conclusions is
illustrated here.

This is the survival of patients in 1684 who were observed. This is the
survival of patients in 1690 who were observed, and this difference, the
improvement in survival of observation patients between these trials, is
as significant as any difference in the trial itself as it was planned
to be analyzed.

But we wondered further could it be due to things before relapse since
much of what I said could have been all post relapse differences, and so
we looked at the largest single subset which is one node positive
patients, and this is from Tom Smith\'s analysis of the single node
positive patients, but basically here for the one node positive patients
in 1684, the one node positive patients in 1690, the survival outcome
for observation patients has also improved.

And so it is both relapse free differences and post relapse differences
that may have confounded these differences between the trials, and we do
not have the explanation for why 16980 did not confirm 1684 completely.

There is certainly a consistent relapse free survival benefit for high
dose interferon as observed between these two trials. There is no
significant benefit with low dose interferon.

There was a lack of a survival benefit with either high doses or low
doses in the 1690 trial, and I said already the post trial crossover may
have explained some of this.

We then had the opportunity to develop a trial based upon the work out
of Paul Chapman\'s and Phil Livingston\'s studies at Memorial Sloan
Kettering with what we thought was the most promising vaccine in 1994.
This trial, based upon the GM2 vaccine work that Phil Livingston had
published, incorporated the Progenics (phonetic) produced GM2 KLH 2S21
vaccine known as GMK, and patients received 96 weeks of this vaccine
compared to the high dose interferon, now the first trial in which we
have compared a new agent against the high dose interferon modality.

These patients, 880, were randomized within 70 days of surgery to
determine if GMK was superior to high dose interferon, and we employed
early stopping rules because we had benefit for interferon already
defined, and we did not want this trial to proceed if the patients
assigned to the vaccine would be at increased risk of death or relapse
in the study.

We employed a cure rate model, as Dr. Ibrahim will more eloquently than
I can describe go through this, and we stratified by numbers of nodes in
entry to this trial.

These are the data that led to the early unblinding and closure of this
study in 2000 when the data suggested that there was both highly
significant survival advantage for interferon over the vaccine and
relapse free interval benefit for the interferon compared to the
vaccine.

For the intention to treat and eligible populations, we have a hazard
ration of 1.49 for relapse. It means that the patients who were assigned
to the vaccine had a 50 percent higher, a 49 percent higher relapse
rate, significant as you see here to a log rank P value of .001 to .004
\-- 00045, both by log rank and by cost analysis.

In terms of survival, we have a hazard ratio of 1.52 to 1.38, again, a
significance of .20 to .009 for survival benefit of the interferon
recipients over the vaccine recipients at the time of early closure of
this study and unblinding in 2000.

These are the published results from last year\'s JC article, interferon
in yellow, vaccine now in red, showing the relapse free survival benefit
of interferon compared to the vaccine.

As you see, the numbers in the interval below show about a 50 percent
higher number of relapses in each of the intervals for the vaccine as
compared to the high dose interferon.

In terms of survival, again, the published results, interferon, and the
vaccine for each of the intervals. Again, a death rate that has
increased for the recipients of vaccines, about 40 to 50 percent higher
than for the interferon alone.

We were interested to look back at subsets because much ado has been
made about the differences in the 1684 trial where the patients with no
nodes involved did not fare well with interferon. This is by all odds
the largest subset analysis that we have had to work with in terms of
node negative patients, and here we have one node positive, two to three
nodes positive, and four or more nodes positive.

And the first conclusion is that there is a homogeneous impact across
all four of these subsets favoring interferon. To our surprise, the node
negative population, a quarter of the patients who entered this trial,
have a significant impact in this subset alone.

This has been a source of confusion, and in fact, a letter to the JCO
next week will be published suggesting \-- and I would like to reiterate
here that this does not mean there was no impact in these groups. It
just means as a subset the node negative population, the T4 node
negative Stage IIB patients derived benefit, which by itself was
significant as analyzed in this trial.

So the largest trial to date, highly significant RFS and OS benefits for
high dose interferon; confirms the 1684 benefits for relapse free and
overall survival.

And I should note here, although I haven\'t put it into this talk, the
evidence that there is no suggestion of an adverse impact of the GMK
vaccine upon either relapse rate or survival in this trial. In fact, to
the contrary, when we look at antibody responders to the vaccine, they
actually almost had a P of .06, a benefit in terms of survival in this
trial.

The benefit was consistent across all of the stratification subsets, and
this then is a summary of the 1684, 1690, and 1694 populations for
subset impact with no nodes involved, one node, two to three, and four
or more nodes, where in 1684 the one node positive population did the
best. In 1690, as I\'ve not had a chance to mention, the two to three
node positive group had the best outcome. And now we see the best impact
and the overview take on this is that there\'s only one subset, the
smallest and one that we knew was unbalanced that has not shown a
benefit. That was in 1684.

So I think the highest level of evidence that we have for evidence based
medicine now, based on the analysis of trials is they were designed and
the primary endpoints of these in a randomized head-to-head setting is
that high dose interferon is an active regimen, is the only one that has
demonstrated consistent relapse free and overall survival benefits
compared to either observation or vaccine.

The benefit of the high dose interferon is consistent across the nodal
subsets in all of these trials.

The obstacle, as you\'ve heard already, is toxicity, and illustrated
here for the patients in the 1684 trial is the numbers of patients who
had the various toxicities listed here in any grade, and what I\'ve
listed here is the percentage of patients for 1684, 1690 and 1694 who
have experienced Grade 3 or 4 toxicity according to fatigue, or about a
quarter of patients may have Grade 3 to 4 fatigue, and where
myelosuppression rose in the fraction of patients who experienced severe
myelosuppression from a quarter to, say, two thirds of patients.

And similarly, the fraction of patients who had Grade 3 to 4
hepatotoxicity rose from 14 to 29 \-- 27 percent in the more recent
trials. We have had no toxic deaths in any of the intergroup studies,
either 1690 or 1694, and the two deaths that were already mentioned
occurred in 1684 before rigorous monitoring of liver functions were
adhered to.

A summary of toxicity then is that all patients have some toxicities
with the interferon. Some patients experience more severe side effects,
including fatigue and flu-like symptoms, neutropenia, abnormal liver
functions, and neuropsychiatric depressive toxicities.

But I think the bottom line is the numbers of patients who complete a
year of this treatment, if they do not relapse, the fraction of patients
who can complete one year of treatment is 24 percent in \-- I\'m sorry
\-- is 76 percent. We only had to stop in 24 percent in 1684; 87 percent
in 1690 completed a year of treatment. That is to say only 13 percent
had to stop and remove themselves from treatment; and we now have 90
percent of patients in the largest study completed to date in the 1694
study who have had to come off treatment due to toxicities.

And so this is a deliverable regimen.

I\'d like to now turn to a pooled analysis that we presented in part to
ASCO, and it\'s been conducted with the intergroup participants from
SWOG, from CALGB, and from the M.D. Henderson in these studies. For
these I\'ll pool the results of the 1684-1690 trials, which were
observation controlled, and we\'ll also include for prognostic analyses
the 1694 and the 2696 studies, which did not have observation control,
as you\'ve already heard.

We\'ll also update the results of these three trials to the April 2001
time point and try to identify factors of prognostic importance, and
that may be related to treatment outcome in these studies.

The methods were that we updated each of the trials because all of these
had their data stored in the ECOG database. Relapse free and overall
survival data were analyzed using two sided univariate log ranked
statistics. The covariates were treated as dichotomous variables or
continuous variables as we had them in the bank, and that log rank
statistics were used for the dichotomous variables. Then a Cox model was
developed.

These are the patients who entered these trials and the intervals of
follow-up that we have. So 1684 is now 12.6 years in median follow-up,
and 1690 is 6.6 years in median follow-up; 1694 is 2.1 years in
follow-up, and the smaller Phase 2 study, nearly three years in
follow-up.

There were 352 patients who were observed for these analyses, 799 who
received high dose interferon, and 474 who received the vaccine GMK.

I should note that we have both the failures and debts separately. We
have the debts for each of these studies plotted and analyzed.

The demographics are the demographics that we expect from Intergroup
Melanoma Studies, two thirds of patients male. A third of the patients
who entered these studies had ulceration of their tumor and half had
recurrent disease, an adverse factor that we will come to in a minute.

So this is the 12.6 year data for the E1684 study in terms of relapse
free survival, and the curve has the flattening that we talked about
before. This is stable out as far as we can go, and it should be noted
again that every patient that entered these trials had elected node
dissection. So failures in this trial are distant failures. This is
distant relapse free survival, which the EORTC has taken as a surrogate
for overall survival.

The 12.6 year data for survival, as you\'ve already heard, has a one
sided P value of .09, but this is all causes of death. So this is
patients who are in their middle 60s because they entered the study at
50 years of age, and all causes of death, whether melanoma or otherwise,
are included in this attrition which exhibits a plateau out as far as
the median that we have here of 12 years, but certainly is not what we
had seen at seven years completely.

The 1694 study relapse free survival has interferon in dark yellow on
top still. The significance is still the one sided P of .05 that we
published, and so this is stable, and there is no survival impact as
there was none as this study was originally reported.

The 1694 study, now more than two years in median follow-up, preserves a
significant P value for relapse free survival. The differences that we
have here in terms of relapses, 159 dead or relapsed on high dose
interferon, 202 on the vaccine pulled up exactly as they were published
a year ago.

The differences in overall survival also remain significant for the 1694
interferon arm, the 1694 vaccine arm, the one sided as it was designed
to be analyzed, .02, but if you\'d like to double it for the two sides
test, .04, retains significance.

For the pooled observation controlled studies we have a significant
relapse free interval impact, and this is interferon at 1684 and 1690
together. Observation in 1684 and 1690 together. The hazard ratio, 1.3,
a 30 percent increment in the relapse risk of patients who were assigned
to observation in the aggregate of these two studies.

The overall survival pooled between these studies where the 1690 study
was larger was a negative study, does not have significance. The hazard
ratio, 1.07.

So looking at prognostic factors that may be identified in this pooled
analysis, the importance of recurrence of disease, highly significant in
terms of relapse free survival. Ulceration of the primary, as is well
known.

Curiously, entry into the 1684 study, an independent adverse prognostic
factor of significance, and the previously reported LDH, depth of tumor,
age over 49, and site entering in.

In terms of overall survival, ulceration remained significant.
Occurrence of disease remained significant, and still the entry to the
1684 study is a significant independent adverse prognostic factor.

Looking for treatment effects, if we ask then from these pooled data
what is the adverse impact of assignment to observation in the pooled
analysis, the hazard ratio, 1.28; the significance, .01. Accounting for
all other prognostically significant factors, ulceration, 1684 trial
entry, and recurrence of disease remained significant as well.

In terms of overall survival, 1.07 for the treatment effect, not
significant, and we retained the 1684 recurrence of disease and
ulceration as already mentioned.

So in summary then, 1684 we have a significant relapse free survival
benefit of high dose interferon versus observation, still evident at a
median follow-up of 12.6 years. Overall survival benefit, significance
is diminished, but there are many competing causes of death that has
eroded this in all likelihood.

Sixteen, ninety, neither relapse nor survival benefit in aggregate, and
overview now: 1694, high dose interferon significantly, superior to the
vaccine GMK for both relapse free survival and overall survival at 2.1
years.

Based on the two sided unit variate log rank analyses, high dose
interferon significantly improved relapse survival compared to
observation. The factors predictive of reduced relapse free survival and
overall survival, ulceration, recurrence of disease, the old study entry
of 1684 and age over 49.

Adjusting for these prognostic factors, we preserve relapse free
survival benefit for high dose interferon. We do not confirm overall
survival benefit.

The highest level of evidence, as I mentioned already, from the three
trials taken together, high dose interferon has demonstrated consistent
relapse free and overall survival benefit compared to either vaccine or
the observation arm.

Pooled analyses show significant improvements for relapse free survival,
but not for overall survival, and the meta analyses that you\'ve heard
about from Dr. Tiwari also support this with a trend to dose effect as
well.

Where we are going, since Karen very clearly pointed to the fact that we
need new studies, is to evaluate more aggressive combinations.
Chemo-biotherapy, for instance, may have an impact which is superior to
that of a high dose interferon. This trial, this SWOG 0008 intergroup
trial testing three cycles of chemo-biotherapy versus high dose
interferon as a head to head comparative Stage IIIB and Stage IIIC
trial.

We would like to improve the therapeutic index of the high dose
interferon modality. We\'d like to ask the question whether one month is
necessary and perhaps sufficient.

So the intergroup 1697 studies testing whether one month alone given to
patients with Stage IIA disease who do not have an effective available
therapy may be superior to observation, and DR. Ibrahim will run through
the statistics of this in a much greater detail. So I\'ll skip over
those now.

If we fail to answer that question about whether one month is the kernel
of the 1684 regimen, we\'ll have to test this in equivalence design. The
1601 has been a trial that has been our first effort at designing
equivalence trials, and Dr. Ibrahim will also discuss this in some
detail.

We\'d obviously like to introduce new cytokines and peptide vaccines for
interferon failures. The trial which is now going on in the intergroup
testing, GMCSF and multi-epitope peptide vaccination is a test of the
potential utility of GMCSF in patients who have failed interferon or
have disease beyond the spectrum of what interferon was designed to
treat originally.

Strategies to develop new adjuvant therapies built from Stage IV
experience are the 1696 trial where we\'re testing multi-FFO peptide
vaccination with or without interferon and with or without GMCSF, and
this trial is more than half completed now to try to pave the way for
new adjuvant interventions of interferons combined with the peptide
vaccination.

Dr. Slingluff\'s trial, E1602, is a multi-epitope peptide vaccine trial
which also may be a source of adjuvant efforts in our committee. We
would like to define the molecular intermediate endpoints of interferon
action and the current trial testing this in terms of the marker EFGF.
Basic fibroblast growth factor is E3601.

So I think with that I\'ll close and turn it over to Dr. Ibrahim to talk
about the statistical design.

DR. IBRAHIM: Thanks, John.

I\'m going to focus much more on trial design for adjuvant studies in
ECOC and really not discuss data analyses, but how we\'ve designed the
trials 1684, 90, 94, and other studies, 1697 and future trials and
current trials that are open now in ECOG.

So just a brief outline of what I\'ll discuss. The cure rate model has
played a very prominent role in trial design for all of these ECOG
studies. So I\'ll talk a little bit about the rationale for using that
model, and we\'ll talk about what it is because it\'s very important in
the studies that we\'ve been designing in all of these ECOG trials, and
then I\'ll talk a little bit about how we design these trials using cure
rate models, and in particular I\'ll focus on designs for 1684, 1690,
1697 and 1694.

Some of these, 1697, for example, are still open. The others are now
terminated and published, and then we\'ll turn it over to
non-inferiority designs using cure rate models, in particular, proposed
Study E1601 is designed as a noninferiority study.

And then we\'ll talk about future trial designs involving high dose
interferon.

Okay. What\'s a cure rate model? The cure rate model is used for
designing studies with any time to event endpoints as the primary
endpoint, such as RFS and OS, and it\'s most useful \-- these models are
most useful when a plateau is reached in the survival curve after a
sufficient period of follow-up.

And we have observed in these ECOG studies in adjuvant melanoma studies
this plateau occurs usually after five years of follow-up, and as an
example, we see here in 1684 this is based on the updated data. We see
that about after five years of follow-up a plateau starts to occur in
the survival curve for both of the arms, and it\'s important then in
designing trials to try and capture this plateau because the behavior of
the right tail of the survival curve really is important to characterize
in trial design, and this is exactly what the cure rate model tries to
do.

And we see the same behavior even with respect to overall survival. So
regardless of endpoint, we see this plateauing effect occurring in all
of these adjuvant melanoma trials.

The same thing for 1690. Relapse free survival, we see this plateauing
effect in both of the interferon and observation arms.

So the cure rate model basically works like this. It assumes that the
study or the population can be subdivided into two subpopulations, those
that are cured and not cured, and the word \"cured\" here is being used
loosely to just mean that a plateau occurs in that particular time to
event.

So it\'s relevant to use the word for relapse free survival. All it
means is that a plateau occurs after sufficient follow-up.

So the subdivided populations then consist of a proportion of patients
who were cured. We\'ll call that proportion pi, and a proportion of
patients not cured. We\'ll call that one minus pi.

And the proportion that are not cured experience events according to an
exponential model with a hazard rate lambda, and then one can write down
the probability of surviving beyond a certain time point as a mixture
between those that are cured and not cured, and this second bullet here
then gives the survival function for the cure rate model.

And so one can view SFT as representing the vertical axis in the
Kaplan-Meier plot, for example.

So just to see how things work here, pi equals .26 means that 26 percent
of the population is cured and 74 percent are not cured. Pi equals zero
means that zero percent are cured, and then this just reduces to the
exponential survival model, and these are the models that have been
traditionally used to design both adjuvant and metastatic disease
trials.

And so we\'re trying to go beyond that now, and the exponential model
then is a special case actually of the cure rate model.

And we\'ve found the cure rate model to actually fit the data better
than an exponential model when this plateau actually occurs in the data,
as did for 1684. So it turned out that once the 1684 trial was
unblinded, the cure rate model actually fit the data better than an
exponential model, and that\'s what led us to design 1690 using a cure
rate model.

One of the nice properties of the cure rate model is that if one uses
the log rank test to design the study, the cure rate model actually has
nice properties and yields high statistical power when this test is used
to design the trial.

Okay. So now what I want to do is review ECOG Study 1684, 1690 and 1694,
and talk about how these trials were designed and then move on to future
designs of trials.

Sixteen, eighty-four, as John mentioned, was a two arm study of high
dose interferon versus observation, and here in the design of this
study, since we had no previous data to guide our design, an exponential
model was used to design the study since there was no prior experience
to guide the design. Four years of accrual were assumed, three years of
follow-up, and a sample size of 285 gave 83 percent power to detect a 50
percent improvement in median RFS from 1.5 to 2.25 years.

Sixteen, ninety was a three arm study involving high dose, low dose, and
observation, and this was the first adjuvant melanoma study in ECOG that
used a cure rate model in its design, and the cure rate model was based
on the E1684 experience, which I\'ll discuss in a moment.

In this study then we had four comparisons of interest, high dose versus
observation, and with respect to both of these endpoints, and low dose
versus observation also with respect to both of these endpoints and a
one side significance level of .025 was used.

And the way we designed 1690 is that we fit a cure rate model to the
1684 data and obtained estimates of the cure rate and the hazard rate
for those not cured, and so for the RFS endpoint, the estimate of the
cure rate for the observation arm was 26.4 percent for the 1684 data and
32.5 percent for overall survival, and the estimate of the median
relapse free survival for those not cured was about a half year for RFS
and 1.32 years for OS.

And so these numbers then were used to design 1690 and we fit the data
both to the observation arm and to the high dose interferon arm, and the
cure rate for the high dose interferon arm for 1684 was estimated to be
27.9.

And so this led to the following design. We assumed four and a half
years of accrual, two and a half years of follow-up, a sample size of
625 yields 81 percent power for RFS to detect a ten percent absolute
increment in the cure rate, and a 50 percent relative increase in median
time to event among the non-cure group.

And these were the estimates observed in 1684. So they weren\'t coming
out of a vacuum, and the same increments for the overall survival
endpoint giving 82 percent power.

So precisely here at the known alternative hypotheses for both of these
endpoints. The cure rate under the null hypothesis, 26.4 percent. This
was, again, the estimated cure rate from the observation arm. Median
time to event for not cured is 6.9 months, and under the alternative,
this is the high dose arm of 1684, 36.4 percent and 10.4 months, median
time to event for the high dose interferon arm, and similar increments
for the overall survival endpoint.

So these were the design specifications then that were based on fitting
the 1864 data to cure rate model, and then we used a sequential
monitoring plan, and we actually \-- any Phase 3 study in ECOG involves
a sequential monitoring plan. So we use that for 1690, which four
interim analyses were planned at corresponding equal increments of
statistical information.

So these two tables give the sequential monitoring plans for the four
comparisons for both endpoints, and we see here that four interim
analyses were done, and this column is the information time, which is
just a fraction of the number of events at each interim analysis. So 65
over 252 is .258, and so forth.

The third column is the nominal significance level and the same
information for the other comparison, and here since E1690 and 1694 both
had RFS and OS as primary endpoints, we line up the analyses to
correspond to the same chronological time. Since the events were
occurring faster on the endpoint of RFS for these two studies to be
analyzed at the same chronological before the DMC, the information times
would be slightly different.

Okay. So let\'s then move on to 1694. Sixteen ninety-four was a two arm
study comparing GMK to high dose interferon, and this was the first
melanoma trial in ECOG using HDI as the control arm.

This was also designed as a superiority trial and a cure rate model was
also used in the design, and one sided significance level of .025 and
the cure rate at median time to event for the high dose interferon arm
were estimated from the 1690 data.

So the design specifications for 1694 actually came from fitting a cure
rate model to 1690. So the assumptions for the design were 3.3 years of
accrual, two years of follow-up, a total sample size of 851 patients led
to 86 percent power for RFS, 80 percent power for OS, and this, again,
was based on a ten percent increase in cure rate and 15 percent relative
increase in median time to event for the non-cure group.

And so specifically here with the design specifications, these cure rate
percentages were being estimated from the 1690 data, as well as the
median time to events for the high dose interferon for both relapse free
and overall survival. And the increments that we specified were similar
to those for 1690.

Again, here is the sequential monitoring plan for 1694. Four interim
analyses; again, information time. The expected number of relapses under
the alternative, and both 1684 and 1690 and 1694 were designed with
O\'Brian-Fleming upper boundaries for rejecting the null hypothesis, and
that\'s what these boundaries were at each of these interim analyses,
and this was the nominal significance level corresponding to that
boundary.

So, again, RFS and OS were primary endpoints in this trial. So to line
up these interim analyses at the same chronological times, the
information times will be slightly different. So the sequential
monitoring plan was driven by overall survival here, and the goal was to
try to do the interim analyses at equal increments of statistical
information, 25, 50, 75 and 100 percent.

Okay. Now we move on to 1697. Sixteen, ninety-seven is a trial that\'s
still open. It hasn\'t terminated and is still accruing patients, and it
involves a different patient population than 1684, 1690, or 1694.

In particular, 1697 involves the T3, as John mentioned, for the U.S. and
for NCIC and Australia, T3NO, T4NO, and NET and N1a, node one positive
patients.

And so this is the first ECOG trial for this patient population
actually, and it was a two arm trial of one month high dose interferon
versus observation, and it was also designed as a superiority trial.

Again, the primary endpoints are both RFS and OS, and again, a cure rate
model was used in the design with a significance level of .025. The
sample size of 1420 patients is based on three years of accrual, three
years of follow-up. Eighty-eight percent power for both RFS and OS to
detect a seven and a half percent increase in the cure rate.

So this trial design involved an increment of less than ten percent, and
a 15 percent relative increase in median time to even for the non-cured
group.

And so here\'s a summary of the design specifications for the cure rate
model. We notice here since this is a slightly healthier patient
population than 1684, 90 or 94 the estimates of the cure rate were
higher than these studies, and in particular, actually these estimates
were coming from the node negative and node one positive patients in
1684 and 90. So we fit a cure rate model to that subset and obtained
these figures from that subset.

And the same thing with the median time to event. These figures were
coming from the subset of patients on 1684 and 90 that were node
negative and node one positive.

Here\'s the sequential monitoring plan for 1697. The same kinds of
numbers as before, except the one distinction here is that with
healthier patient populations and especially when you expect this
plateau to occur in the survival curve, the events are going to start
occurring much less frequently once you get beyond a certain period of
follow-up, and so we inserted an extra interim analysis here so that
there wouldn\'t be a long time between the third interim analysis and
the final analysis.

And so here we inserted another interim analysis at 90 percent
information so that there wouldn\'t be such a long wait in between
interim analyses.

Again, the same story for OS. The boundaries here are O\'Brian-Fleming
upper boundaries and the nominal significance levels correspond to
those.

One of the critical issues now in ECOG trial design is conditional
power, and conditional power considerations are essentially playing a
prominent role in any ECOG trial, especially ones in which you might not
expect the experimental arm to be doing much better than the control
arm.

So the idea of conditional power, it\'s a conditional probability
calculation, and it\'s the probability of observing a significant
result, given the current data and the specified alternative under the
statistical design.

So what this conditional power calculation allows us to do is
essentially compute the probability of getting a significant result at
full information at the final interim analysis, given the current data
and the specified design parameters under the alternative.

And again, the idea behind conditional power is it allows us to stop the
study early if the experimental therapy is not much better than control,
and one issue that I\'ll discuss later is the timing of the conditional
power calculation is critical, I think, because we want to do this
calculation when we have sufficient follow-up in the trial.

So as I noted in most ECOG studies now, we implement traditional power
calculation as part of the interim monitoring plan, and in particular
traditional power is very important in trials that have observation arms
and trials that are of the form A versus A plus B, that is, a regimen
called A versus A plus something else.

And clearly here the A plus something else is generally more toxic and
more expensive than A. So we want to stop the trial earlier if A plus B
is not much better than A.

So these are two scenarios under which conditional power is very
important, and 1697 conditional power was part of the monitoring plan,
and we see that conditional power plays now a very prominent role in
these types of studies, as well as noninferiority designs which I\'ll
discuss now.

So noninferiority designs, I think, will play a prominent role in future
designs of ECOG, and especially future designs that involve high dose
interferon as the control, and in particular, we envision future trial
involving HDI and a vaccine or HDI and a combination of HDI and a
vaccine, and my conjecture is that these trials will be designated as
noninferiority designs rather than superiority designs.

We learned a great less from 1694 that perhaps it wasn\'t the best idea
to design it as a superiority trial. So within the context of the cure
rate model, these designs can be constructed by essentially taking small
differences in the cure rates, and I think that\'s where the cure rate
model really has a great benefit here, is that you can dictate
equivalence trials essentially by specifying the cure rate difference.

Again, the cure rate difference is the tail area in the survival curve,
and I think most people would agree that that\'s where the important
action is. We want to know what the tail behavior is in the two arms
after a sufficient period of follow-up, and that\'s what would dictate
then in an equivalence trial.

So you don\'t get it for free though because the sample size is
increased dramatically when the cure rate differences become small, and
so there\'s a price that one pays in the sample size. So there\'s the
issue of feasibility versus how small of a cure rate difference you want
between the two arms in an equivalence trial, and so typically in
noninferiority or equivalence trials \-- I\'m using these two words
interchangeably here \-- the higher significance level than a nominal
level of .05 is acceptable to use in these types of trials.

Sixteen, oh, one is a currently proposed study in ECOG, and it involves
a slightly different patient population than 1697. It involves T4NO,
NET, and N1 and N2 patients. So it involves one node positive and two
nodes positive, and this is a study that\'s currently being proposed in
ECOG.

It\'s designed as a two arm, noninferiority trial of one month high dose
interferon versus one year in which the primary endpoint is relapse free
survival. And so when designing a noninferiority trial, you need a
definition of noninferiority, and that depends on the disease site.
That\'s disease site specific, as well as patient population specific
and study specific.

And the way we\'ve defined it here is that we\'ll declare one month
noninferior to one year if there\'s less than a 25 percent absolute
difference in median RFS for those non-cured and less than a three
percent absolute difference in the cure rate between the two arms.

So these are the two design parameters that one needs to specify in a
cure rate model, and we claim that the much more important parameter is
the cure rate rather than the median time to event in those not cured.

We really are willing to allow a bigger difference in the median time to
event for those not cured, but are not willing to specify a large
difference in the cure rates. In other words, we want the tails of the
survival curves to be virtually closed, and that\'s what we\'ll declare
equivalence.

And so that\'s the way we\'ve defined it for 1601, and equivalence
trials are ones in which you allow the significance level to be higher
than the .05 level, but ones in which you desire a higher power than the
usual 80 percent. So 1601 was designed with 95 percent power and using a
one sided significance level of .075.

And we assume four years of accrual, six years in follow-up. A sample
size of 2,780 patients yields 95 percent power for RFS. To detect this
three percent increase in cure rate between one month and one year of
high dose interferon and the 25 percent increase in the median time to
event for the non-cure group, and again, here is a summary of the cure
rate and median time to event.

We assume 63 percent cure rate on the one year high dose interferon arm,
60 percent on one month, and .9 years on one year, and .65 on one month.

Again, we use a sequential monitoring plan in which we use an
O\'Brian-Fleming upper boundary for early stopping in favor of
superiority of the one year interferon, and so we\'ll stop early in
favor of one year using an O\'Brian-Fleming upper boundary.

Again, we insert five interim analyses, one year at 90 percent
information. However, conditional power then will be used as the lower
boundary to declare equivalence or noninferiority.

So the conditional power will be computed to determine the
noninferiority of one month relative to one year, and again, this is
based on RFS endpoint, and the timing of the conditional power
calculation is critical here because conditional power will essentially
dictate whether the one month high dose interferon is noninferior to one
year. That\'s what is going to dictate noninferiority here in the trial
design.

And so the timing is important, and the first time the conditional power
will be calculated for this study is at 75 percent information and then
again at 90 percent information, and the rationale behind that is that
we want to allow for sufficient follow-up, and the 75 percent
information is one where you would expect the accrual goal to be
attained for the study.

So it makes sense to do the first conditional power calculation at that
information time.

This table here gives various sample size scenarios when you vary the
cure rate percentages, as well as the difference in the median time to
event. So this first column represents a cure rate difference between
two hypothetical treatment arms. The second column represents the
difference between the median time to event between the two treatment
arms, and third column gives the induced sample size that would be
required.

And so the main thing to glean from this table is that as one decreases
the cure rate, so if we just focus on the last row here for a moment,
ten percent difference in cure rate, 15 percent absolute increase in
median time to event, again, requiring 95 percent power, say, leads to a
sample size of 760, and as we fix this increment at 15 percent and
decrease the cure rate, we see that the sample size more than doubles as
we decrease the cure rate by a moderate amount.

So once we start getting in the five percent area, we here that it\'s
essentially tripled, and then here at three percent it\'s quadrupled.
And so there\'s a big price to pay in terms of sample size if one wants
to do noninferiority studies.

The price is not nearly as much if we fix the cure rate and decrease the
difference in median time to event. So here the differences are only in
hundreds of patients.

So in other words, if I just look at the difference in cure rate of
three percent and look at these increments here, there\'s not much of a
price to pay at all, and so the cure rate parameter is the one that
really drives the sample size and is one that\'s critical in designing
noninferiority studies.

Okay. Future trial designs then we envision would be ones that would be
similar to those of 1601. So noninferiority designs of the type used for
1601 will be used, we envision being used for future Phase 3 trials
comparing investigational therapies to high dosage interferon, and
again, the definition of noninferiority is critical.

There is not a benchmark or a conventional definition of noninferiority.
It depends on the trial, and it\'s something that differs from trial to
trial.

But the bottom line is that in any non-inferiority study with these cure
rate models needs small cure rate differences. And conditional power
also plays a key role in these designs, noninferiority studies, and as I
mentioned for 1601, as well as 1697.

And we envision the next ECOG adjuvant Phase 3 trial will be something
like high dose interferon versus the best vaccine from 1696 or the best
vaccine \-- actually this John called the 1602. This is the 12 peptide
vaccine trial, Phase 2 trial, that\'s currently being proposed for other
regimens, combinations of high dose interferon and vaccine.

This is where we\'re headed in ECOG, and we envision trials of this
sort, of high dose interferon versus these as the control, and these
being the experimental arms to be noninferiority studies or equivalence
trials.

And one can use the methodology similar to 1601 to design these trials.

One last comment that I\'d like to make about future trial designs is
that we\'d like to also investigate Baysian and monitoring schemes for
future trials. I don\'t want to get into the philosophical issues of
Baysian design and non-Baysian design here, but I do just want to
mention that Baysian designs offer special advantages other designs may
not have.

So one can do a Baysian design within the context of this cure rate
model, and one of the advantages that Baysian designs have over these
traditional designs that we\'ve been discussing thus far is that they
allow us to formally incorporate historical data into sample size
calculations.

And the reason this is important in the context of melanoma is that
we\'ve got quite an abundance now of historical data for 1684, 1690, and
1694 for the high dose interferon arm. So this is one advantage of these
types of designs, is that they allow us to directly incorporate this
information into the sample size calculation.

Another advantage is that they allow us to do continuous monitoring
without paying a penalty in the Type 1 error or the significance level.
So one of the practical advantages of this is that one can do an interim
analysis at every DMC meeting, for example, rather than way until a
certain information time has been reached.

And so this is what we mean by continuous monitoring, and this is one of
the advantages that Baysian design has to offer.

And, again, as I mentioned, we have now an abundance of historical data
on high dose interferon from these three studies, and so one can use the
data from these studies to construct appropriate prior distributions for
the effect of the high dose interferon using these data, and then these
distributions can be incorporated into the sample size calculations and
will often result in greater precision and smaller sample size than the
traditional designs.

And as mentioned a moment ago, Baysian interim monitoring rules can be
easily developed, and what we would do then at each DMC meeting is just
compute the probability that the treatment works, compute the posterior
probability that a given treatment is better than the control treatment,
given the current data, and this can be reported at every DNC meeting
without an issue of inflating the significance level, and this is one of
the practical advantages that I see in doing Baysian design.

And that\'s all I have.

CHAIRPERSON NERENSTONE: Thank you very much.

I would like to ask you to hold your questions until we take a break. We
should be back at 10:45. Thank you.

(Whereupon, the foregoing matter went off the record at 10:34 a.m. and
went back on the record at 11:05 a.m.)

CHAIRPERSON NERENSTONE: I\'d like to start by asking the Committee if
they have any questions for the presenters this morning.

Dr. Przepiorka.

DR. PRZEPIORKA: Questions for Dr. Kirkwood or Dr. Ibrahim.

Dr. Kirkwood, could you please give us your opinion? Did patients with
locally current disesae have the same prognosis as those with newly
diagnosed disease going into trials when compared node for node?

DR. KIRKWOOD: The prognosis of local recurrence, I think, is
significantly more ominous than for primam presentation. The date from
Urist (phonetic) in Alabama is probably the best for recurrence, now
ten, 15 years old, but I think the prognosis for those are at least as
bad as nodal involvement.

DR. PRZEPIORKA: But for patients with locally recurrent disease and no
nodal involvement?

DR. KIRKWOOD: That includes in the absence of nodal involvement. Realize
that most of the data that I\'m referring to came from an era before
sentinel node mapping, and I think it\'s only now that sentinel node
mapping is being done off of recurrences, but there may be \-- and Dr.
Slingluff and surgeons here may be able to speak to this more directly.

DR. PRZEPIORKA: Dr. Fleming.

DR. FLEMING: Dr. Kirkwood, I\'m trying to sort through, in particular,
the evidence on survival effects, and in the studies you\'ve presented,
the 1694 seemed to be particularly intriguing on survival effect.

You had mentioned in your presentation that you had evidence that the
GMK vaccine wasn\'t harmful, hence, in fact, inducing the different to a
harmful effect by the vaccine. Could you again clarify what that
evidence is?

DR. KIRKWOOD: Three bits of evidence. The first is as we plot the
outcome for the GMK arm of 1694 against the 1684 and the 1690
observation arms, it certainly is intermediate and no worse than those,
and I can present that to you on a slide if you\'d like.

DR. FLEMING: Well if I could just take it one at a time, you had also
clearly made the point at how hazardous those kinds of \--

DR. KIRKWOOD: I agree.

DR. FLEMING: \-- comparisons could be because there are so many factors
that could be confounding that. So that seems to be a fairly
controversial piece of evidence at best.

DR. KIRKWOOD: Right, and the second is when we looked at the hypothesis
that drove the design of the 1694 study, it was that the induction of an
antibody response to the GM2 molecule is potentially favorable to
patients, and so when we actually measured the antibody response at the
end of the first month for patients who entered the vaccine arm, plotted
those who had an immune response and antibody titer above a threshold of
one to 80 versus those who did not, those who had an antibody response
actually did better to a P value of .06 in terms of survival that I
alluded to briefly in my talk.

So those who made the immune response, which was the goal of the
immunization, did better than those who did not.

DR. FLEMING: So what does that tell us in any way about what the vaccine
globally is providing effect or non-effect? Those that are
immunologically different, in fact, would have that immune response,
could have been intrinsically better and would have had a better outcome
so that it\'s not clear when I see those that have the intended immune
response that they do better than those that don\'t, that that provides
me any sense of whether globally the vaccine is helping or harming
survival?

DR. KIRKWOOD: No, that\'s true, and in fact, we have to admit that we
didn\'t have an observation arm. Following 1684, 1690, we decided we had
to compare it to interferon, and we\'ll never really be able to address
this head to head.

So I\'m not arguing that it\'s clear to me that the GMK vaccine is
harmful. It\'s just not clear to me that there\'s any evidence to know
whether the difference that we see that\'s so favorable in that trial
could in some way have been partially explained at least by a potential
adverse effect of the vaccine.

CHAIRPERSON NERENSTONE: Dr. Kirkwood, I don\'t know if you or perhaps
the folks from Dr. Chapman\'s group could speak, but there was also
preliminary data from a randomized controlled trial that made you choose
that particular vaccine to go forward with, and I don\'t recall the
details of that, but perhaps you do better.

DR. KIRKWOOD: Yeah, this is the publication of Phil Livingston for the
GM2 plus BCG trial and Paul Chapman is here. So perhaps he would like to
speak to that, but certainly in that trial there was a trend to relapse
interval benefit. They did not have survival benefit, but there
certainly was no hint of an adverse effect.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: Yes, two questions for Dr. Kirkwood.

First of all, in your Slide 28, which goes to the number of patients who
discontinued the interferon regimen for toxicity, is that different for
patients who discontinued interferon for a year or did not complete a
year for any reason?

Because I think those numbers are low for the number of patients who
could discontinue the year interferon.

DR. KIRKWOOD: That was discontinuations for any cause other than
relapse.

DR. BLAYNEY: Okay. Thank you.

Secondly, if one hypothesizes that as you showed in the 16, then your
earlier trial or in your second trial that the salvage for alpha
interferon once relapsed may have contributed to the survival benefit
and thus the dilution or the equivalence of the various arms in your
later trial, how many in the early trial, the 1684 patients, received
alpha interferon who were in the control arm and received alpha
interferon when they relapsed?

DR. KIRKWOOD: Yeah. We\'ve gone back through the charts of the 1984
patients, and no one who failed observation then crossed over to receive
interferon. It was, of course, not approved at that point in time, and
it\'s subject to the retrospective review of the charts for this.

And since your next question may be if that\'s the case, what happened
in 1694, we\'ve just completed a sweep of the 880 charts from the 1694
trial for exactly that information. I don\'t have that right now, but I
suspect it was much less for 1694 given the prevailing negativism about
interferon after 1690.

DR. BLAYNEY: So it might be a reasonable \-- a statement is reasonably
made that interferon at time of relapse is a reasonable salvage
treatment, which might extend survival in patients who are, as you\'ve
told us, destined to die because they have relapsed.

DR. KIRKWOOD: I think that\'s a hypothesis that can be taken from the
1690 study.

DR. BLAYNEY: Thank you.

CHAIRPERSON NERENSTONE: Dr. George.

DR. GEORGE: You showed us information about toxicity tables, and I
don\'t think we had in our materials nor did you present today anything
about quality of life kinds of studies. Have you done these as part of
these trials or are you planning to?

DR. KIRKWOOD: Yeah, we\'ve done and published in 1996 in JCO a study of
quality of life, a Qtwist retrospective analysis of 1684 patients which
showed benefit in terms of quality of life and quality adjusted life
years gained which favored interferon. We actually presented those to
the committee in July of 1995 as the basis of the first approval.

We have completed studies of both Qtwist and Qtility, the time utility
analyses that Kerry Kilbridge, Chip Cole had been doing. The latter will
be presented or submitted for ASCO this year. The former were published
in the fall of last year by Kerry Kilbridge.

DR. GEORGE: These were retrospective kind of? I\'m not sure.

DR. KIRKWOOD: Yeah, the Qtwist analyses were all retrospective analyses
of the chart data for toxicity. The utility analysis was a study of a
separate population of patients who were asked given the likely
toxicities of interferon, how would they weight time with the toxicity
as opposed to time with relapse of disease, and from those I think we
learned that the value of time with relapse of disease is so poor that
the patients favored the toxicity on that basis.

CHAIRPERSON NERENSTONE: Dr. Sledge.

DR. SLEDGE: John, actually I really appreciated your presentation which
I thought was quite clear. Listening to your colleagues in the melanoma
community and the advocacy folks, however, what I hear from them is that
while they\'re willing to at least possibly buy the relapse free
survival advantage, they have a fairly high degree of skepticism about
the idea that we have a proven overall survival advantage, something
that I\'d say actually your pooled analysis may provide some further
skepticism about, and that even if there is a small advantage from an
overall survival standpoint, I\'ve heard folks in your community doubt
whether or not it might be worth it for the average patient just from a
toxicity standpoint, rather that if, say, for instance, we were looking
at polio in 1955, we were being required to randomize patients to the
Salk vaccine versus an iron lung.

Do you think that\'s a reasonable position? And do you in your heart of
hearts think that we should be requiring all future trials to involve
high dose interferon as a standard arm? Because I think that\'s really
what we\'re being asked here.

So the first question, I guess is how much do I take the negative
comments of some of my colleagues who are venerable members of the
community that preceded us today, and I think that you could pick from
the cooperative groups that have actually done the studies an equal
number who would be ardent supporters of the survival impact.

I think in my heart of heart if you ask me do I think there\'s a cure
fraction for high dose interferon, my answer is yes, and I think that\'s
the basis of the statistical design for all the studies after 1684.

So I think that cure fraction is enough for me to believe that this is a
reasonable standard against which all future treatments that are
potentially going to be superior ought to be compared.

Do I think that patients who are either medically unable or unwilling to
participate in this should not have access to other therapies? No, and I
think that some compromise of the sorts that you\'ve heard about, you
know, some of those that Dr. Slingluff has presented, for instance,
might well be reasonable intermediate grounds.

I think that the treatment of patients is, in fact, as we heard from Dr.
Tiwari 60 percent of patients across the country are actually getting
treated. I\'m actually surprised, but I think that\'s a reasonable
penetration. It\'s certainly not a dismal and very sparse use of high
dose IL2 that Dr. Rosenberg talked about, which you know, clearly is
another paradigm here.

I think that trial design in Phase 3 randomized controlled trials will
establish if anything else is better or anything else is active. Right
now, this is al we\'ve got.

CHAIRPERSON NERENSTONE: Dr. Vanderpool.

DR. VANDERPOOL: Dr. Kirkwood, I\'m seeking to make some sense about your
rhetoric over against some of your statistics. I\'m just puzzled a bit
by it.

In the printout of your slides, on C13 you say that both relapse free
survival time and overall survival were significantly prolonged with
high dose interferon, but then at C33, I note that over 12.6 year period
95 persons died without treatment and 93 died with interferon.

And then you can look through the rest of those statistics and see
similar actually very small differences. E1690 had 103 die without
treatment, 108 die on interferon, and then the totals are similar.

So I see a small, very small numbers here, and I don\'t know how to
match that up with your significantly prolonged rhetoric.

DR. KIRKWOOD: Well, I think the significantly prolonged was in the
analysis of the randomized head to head, Phase 3 trials as we calculated
events per unit time and analyzed these by log rank analysis as they\'re
designed to be analyzed. Those event rates were different both in 1684
and in 1694, and the numbers at the bottom of the survival curve and the
numbers at the bottom of the relapse curve for 1694 are perhaps the most
graphic for this.

The overall analysis for trials when 13 years\' median have elapsed
since patients were 50 when they entered these trials is tallied, I
think, best, is likely to come together. Certainly if we get out to 20
years with median follow-up, I suspect the curves will all be together
because, you know, as some of my colleagues from England have said, live
is a banana. I mean, it all comes together if we follow things far out
enough.

In this particular initial analysis, we were seven years in median
follow-up. That was when the P of .023 was found for the significance of
the survival impact analyzed as the study was designed to be analyzed,
and I think that the fact that they come together somewhat at 12.3 years
of follow-up and will doubtless come together as we follow things out
farther later doesn\'t surprise me. I mean, those are all events. The
survivals, again, for ECOG and for all cooperative group studies tally
all events, deaths due to cardiovascular disease, strokes. I mean, many,
many other things are competing for melanoma at the time point that
we\'re seeing these curves come together.

DR. VANDERPOOL: And to also repeat one of the comments by Dr. Sledge
just now, I suppose what this committee will be asked to decide is at
what cost do those increased survival times afford.

You can procure increased survival and disease free status, but at what
cost must that be procured?

CHAIRPERSON NERENSTONE: Just a point of information. I wanted to remind
everyone that we are actually not going to be voting. This is a
non-voting discussion, and this is completely advisory to CBER. So just
a point of information.

Dr. Nelson

DR. NELSON: I\'d partly like to follow up on the comment about the high
dose interferon as a control group and ask really two questions. The
first is the reason why then 1697 was designed in a way that, in fact,
there was no group that included the high dose interferon as tested
within the earlier trials, that that\'s a one month course raising
similar issues, but not to get into a different political quagmire of
the low dose AZT within the international community.

Also, the follow-up question from a design is why one would be content
with a non-inferiority design when, in fact, if you look at the overall
statistics, even if you accept the nine month extension and benefit, I
certainly would be interested in finding something better than that.

So both of those questions I\'d be interested in from a study design
perspective.

DR. KIRKWOOD: For 1697, the design targeted T3 node negative patients in
the main. This was targeted upon intermediate risk patients for which no
therapy has ever been shown to have survival benefit.

So that was the specific reason we included patients below the risk
category for which we had shown benefit in 1684 before that.

The design for 1697 is not equivalence. It is superiority. It is seeking
a superiority of 7.5 percent in cure rate, and so we agree with you. It
should not be equivalence with observation. We\'re looking for
superiority to observation.

DR. NELSON: I guess I was struck though by at least the ending of Dr.
Ibrahim\'s presentation where he advocated that perhaps noninferiority
studies would be what ECOG would select going forward, whether that
should be the standard.

DR. KIRKWOOD: Yeah, I think that really meant for the groups for which
we think there is benefit, and 1601, for instance targets node positive
patients and T4D primaries that are exactly the group that we see the
benefit in 1694.

CHAIRPERSON NERENSTONE: Dr. Albain.

DR. ALBAIN: Yeah, Dr. Kirkwood, I\'d like to come back to your life is a
banana comment, if I may. I\'ve been troubled a little bit by some of
the discussions comparing these results with Tamoxifen adjuvant data,
and if you, in fact, look at the worldwide overview for Tamoxifen, five
years receptor positive, no treatment controls. It\'s not a banana. It
does not come together. In fact, it\'s robustly separated with years of
follow up, and these are elderly women, competing causes of death, also
treated on relapse with numerous other active agents.

So I don\'t think it\'s quite the same scenario. I\'m not disagreeing
that you\'re not seeing a survival effect here, but I don\'t think it\'s
similar.

CHAIRPERSON NERENSTONE: Dr. Fleming.

DR. FLEMING: Just following that up, the FDA also drew our attention to
the 5 FU/Levamisole, and life certainly isn\'t a banana there. The JCO
report update, I think, in \'96 or \'97 that presented the seven year
follow-up showed a very large, substantial, I think, 57 versus 43
percent difference in survival.

Speaking of, however, the banana configuration, one of the things I\'m
really trying to get better sense about is the nature of the effect on
survival. The argument that\'s been made, I believe, if I\'m
understanding it, is we\'re dealing with a setting here where there\'s a
cure rate model or what we might be dealing with is effects on survival
that could be mediated through, in part, an achievement of cure which
would mean that if we take \-- and I found very helpful and informative
the FDA meta analysis that said individual studies in this setting
really are inadequately powered to address survival. Let\'s look at the
aggregation of data.

That aggregation says there\'s about a ten percent reduction in risk.
Well, is this reduction of risk essentially representative of transient
benefit or is this really representative of being able to achieve a cure
and sustained long-term benefit in a sub-cohort of the population?

If we go to \-- and I don\'t think Dr. Tiwari numbered his slides \--
but if you go to his slide on the odds ratio for survival, one finds
that all of them go in the right direction, although several of them are
relative risk estimates just barely below one, and then the more
impressive ones are the original 1684 trial from ECOG and the 1694
trial, along with the Cameron studies and the French study.

And what\'s interesting is when we look at your updated data in 1684, it
does show more a banana type configuration, although granted it doesn\'t
come back together until about ten to 12 years, but if you look at the
data that Dr. Tiwari presented on survival for the Cameron study, those
curves definitely come back together at about five to six years.

And if you look at the data from the French study, those curves also
come back together, and then the remaining positive study is the one
that I\'m already struggling a bit about that we talked about earlier,
which was the 1694 trial against the vaccine, and it\'s unclear to me to
the extent to which that difference could at least have partially been
due to an adverse vaccine effect.

So the bottom line is if we take a look at these odds ratios for
survival in Dr. Tiwari\'s summary, the four studies that tended to show
the signal here, studies that seem to show a loss of the benefit, and so
is there, in fact, a basis for us saying here we\'re dealing with
something more than a ten percent risk reduction that\'s a transient
effect? Is there, in fact, evidence that we can use to say there is, in
fact, an increase in cure that should translate into a true long-term
sustained benefit?

CHAIRPERSON NERENSTONE: Other questions? Dr. Brawley.

DR. BRAWLEY: The two last questions brought this up. When I treat breast
cancer adjuvantly with Tamoxifen or even with other chemotherapies, if I
treat 100 women, I actually have an estimate of how many women I\'m
actually benefitting in that 100. It\'s usually going to be a small
number because there\'s a large number who will not relapse no matter
what you do. So they\'re getting adjuvant therapy unnecessarily, and
there\'s a group that will relapse even though they get the adjuvant
therapy.

So I treat 100 women with the premise that I\'m going to help some
number, usually 15 or 20. Is it possible that figure out approximately
how many people benefit from adjuvant therapy with interferon?

And then, of course, the last question actually brought up the issue of
what benefit is it. Is it that the disease does not come back or is it
that life is actually prolonged?

But is it possible to quantify the number of people who get this
adjuvant therapy now who don\'t really benefit from getting it and the
number who do?

I don\'t know. Dr. Kirkwood, Dr, Tiwari, can you help me with that?

DR. TIWARI: Well, the reduction in the overall survival from all of the
data is at ten percent. So you would think that ten percent of the
patients will benefit with respect to the survival.

DR. SIEGEL: I think that\'s a relative difference. I think the
difference in the number of patients who never get their tumor again or
at least over ten, 15 is 20 percent relative, but it\'s ten percent
absolute. So there are differences of the meta analysis that suggest
that ten percent more patients have long term survival without evidence
of melanoma.

But closer to four or five percent would be the point estimate on
survival, a relative difference of survival of ten percent, but an
absolute difference of four or five. So may be one \-- again, wide
confidence intervals around that, and we can argue as to whether that is
statistically significant or not, but even if it isn\'t, it may be much
smaller than that amount, but that\'s where the point estimate came out.

DR. BRAWLEY: So are you suggesting that if we treat 100 people right now
for melanoma \-- let\'s be really conservative \-- 80 don\'t benefit
from it?

DR. SIEGEL: Yeah, I think that\'s about right, but it\'s worth noting
like one of our best treatments out there, one that people think is one
of the greatest drugs out there, for example, is thrombolytic therapy in
which we believe that if you treat 100 people with heart attacks with
like TPA, you know, 98 of them won\'t benefit, but you reduce mortality
from seven percent to five percent.

So it\'s probably true of many of our best drugs that, you know, that
ten percent may not be as small a number as you make it out to be or 20
percent or whatever it is.

CHAIRPERSON NERENSTONE: Dr. Kelson.

DR. KELSON: Following up on Dr. Fleming\'s question, I was also looking
at the graphs on page 15 of the presentation. I was equally struck or
maybe more struck by the graph on the bottom of the page. Again,
they\'re not numbered, but it\'s the meta analysis, and I guess this is
an open question to Dr. Kirkwood or others.

The meta analysis looked at two different meta analyses, but if we
looked at survival, in both cases the 95 percent confidence lines either
touched or crossed unity, and that means to me \-- and this is a
question \-- there\'s not a super amount of confidence I have that
you\'re really seeing a true effect.

The effect is modest, as absolutely looked at. The confidence limits are
not that broad around those observations because it is a meta analysis,
which I found very helpful.

But it touches one or crosses one, and that to me suggests a null effect
or at least a possibility of a null effect, and I wonder how that
strikes Dr. Kirkwood and the others.

DR. TIWARI: That\'s true. In our analysis we have a P value of .065, and
the analysis by Wheatley, [et al]{.underline}., gives a P value of .05,
exactly .05. So it is borderline statistical significance.

DR. KELSON: Just following up as a GI oncologist, the colo-rectal
comment and the breast comment, I mean, you don\'t see that when you
look at meta analyses. You know, we\'re not touching one.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: This discussion reminds me of a point I was just thinking
about during Dr. Ibrahim\'s presentation, which is how you would present
this kind of data to make sense to someone trying to make this sort of
decision, and since as a non-oncologist, I only approach this area as a
potential consumer, let me take a stab at that.

I found presenting, for example, a nine month extension of event free
survival more useful than giving me percentages, but in listening it
occurred to me that what you really want to know is what are my chances
of being in the group that\'s going to be cured versus my chances of
being in the group that\'s not going to be cured and will, in fact, have
then nine additional months of life if I\'m in that group.

So as you think about the complexity of weighing those decisions against
the potential toxicity of treatment, you\'re really balancing a number
of different variables, which I don\'t think are fully captured by just
giving me a percentage of ten percent, for example.

And having said that, I guess I\'d be interested to hear if that\'s at
least in the right direction. If we\'re going to put weight on the
informed consent, as some have argued, how would we go about
transmitting this information in a way that makes sense to
non-statisticians and non-oncologists?

CHAIRPERSON NERENSTONE: Dr. Brawley.

DR. BRAWLEY: Well, what I think, and please correct me if I\'m getting
this wrong because, you know, I design clinical trials, but I try always
to go for the statistics to real numbers whenever possible.

I think what we just talked about is if you treat 100 people, 80-plus of
that 100 people derive only the side effects and no real benefits from
the current therapy. Some where ten-plus may derive some benefit. It is
\-- did I \-- am I being correct? Okay.

CHAIRPERSON NERENSTONE: Dr. Carpenter.

DR. CARPENTER: One distinction to be made is whether this is an absolute
benefit or a relative benefit. Now, understand that the ten percent
which is discussable since the confidence limits overlap with one is a
relative benefit.

DR. SIEGEL: The percent that turns out that approximately the relative
benefit and overall survival in the absolute benefit on relapse free
survival. So they\'re 20 and ten or ten and five roughly, depending on
\--

DR. CARPENTER: So it would be five percent would be the number you\'re
speaking of?

DR. BRAWLEY: Oh, I\'m doubling just to give the drug benefit of the
doubt.

(Laughter.)

DR. CARPENTER: That would suggest that 95 percent of the people.

DR. FLEMING: Just to be explicit, if you had and we often hear the
figure about 65 percent five year survival for this cohort, if in that
cohort that had 65 percent five year survival, if you provide ten to 11
percent reduction in the hazard ratio, the relative risk, that
translates to improving that survival from 65 percent to 68 percent.

Does that help\>

DR. BRAWLEY: I was still doubling the number to try to give the drug as
much benefit of the doubt as possible, but, yeah, it unfortunately is
very helpful.

CHAIRPERSON NERENSTONE: Dr. Carpenter \--

DR. SIEGEL: Well, we\'re talking 40 percent survival. So most of these
cases \-- so the ten percent relative changes is somewhat larger.

CHAIRPERSON NERENSTONE: Dr. Carpenter, did you have another comment?

DR. CARPENTER: I just think that some idea of the absolute benefits are
helpful, and the position that most of us end up in, which is talking to
a person, and particularly with the new staging system, one\'s ability
to estimate prognosis is fairly precise, if I understand it, given these
new numbers.

And you\'re going to know. It\'s helpful in trial design because you\'re
going to have a pretty good idea of the prognosis of the people that you
enter. So you know how to affect it, but to me the number that means the
most is the absolute benefit in what Dr. Brawley is calling real
numbers, I think, but it\'s probably on the three to five percent range
to balance against a year of toxicity.

And it\'s apparent from the discussion that how the toxicity is viewed
is very different to different observers.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: I continue to follow on this notion of how it would be
understandable in terms of an informed consent process. What I\'m
hearing is if I fell into this particular risk category without
interferon I would have a roughly 65 percent chance and with it I would
have a 68 percent chance of being in the cure group.

So you\'re basically telling me that I want to trade off a three percent
chance? I mean \--

DR. SIEGEL: These numbers aren\'t that hard. I don\'t want to address
the questions, but let me just provide some clear numbers. If we look at
relapse survival, this 1684 is pretty representative of what we find
from the overall study, from an overall analysis.

What you can say as you go out to the five to ten year range to put into
real numbers is that maybe it was the three or five year follow-up, but
the differences hold up pretty closely, and that is that you had 41
percent of patients alive without any recurrence or any evidence of
disease if they got interferon and 32 percent alive without any evidence
of disease or any recurrence if they didn\'t get interferon.

Now, that is in absolute terms a nine percent difference, and we said in
our overall meta analysis maybe that\'s a ten percent difference, and in
relative terms, that\'s about a 20 percent difference because nine is 20
percent of 41 or 30 percent of 32, whatever.

So that\'s the size difference we\'re talking about in relapse free
survival. If you look at survival curves, what you find is that in the
observational group there\'s a few more people who are alive who have
had tumors. Because when you look at overall survival, you\'re not just
looking at alive without tumor or what in design features was termed
cure, but you\'re adding also those who are alive who had tumor, and it
turns out there\'s more people alive with tumor in the observational
group. So that makes those differences smaller, approximately half of
the size.

DR. CARPENTER: That\'s certainly true. I think one of the \-- my sense
is that one of the things that\'s pulling at us is this difference
between relapse free survival and overall survival. Most other therapies
for approved adjuvant therapies for malignant diseases, such as, let\'s
say, breast cancer and colo-rectal cancer because those are perhaps the
least controversial, are based on substantial differences in overall
survival, not just on relapse free survival.

And I think what we\'re hearing here is that there is a probably
substantial and fairly agreed upon difference in relapse free survival
that\'s supported by virtually every analysis that we\'ve heard, and a
smaller discussable, much less confident benefit in overall survival.

So in terms of how one would phrase that to a patient, I\'m sure that
it\'s observer dependent, but usually when I discuss adjuvant therapies,
I talk about the chances of being alive at a certain point because we
can discuss relative merits and benefits of toxicity and extension of
relapse free survival, but death is pretty quantitative event.

This treatment is going to make you live longer by a substantial amount
of time. Then it gets to be very focused discussion about how much
toxicity it\'s worth for you to take.

If, on the other hand, there\'s a lot less confidence in the true
extension of survival, then the toxicity to me at least would play a
much larger role.

So I think it\'s helpful to get at the absolute numbers wherever we can,
and to make sure we\'re talking about the same thing when we talk about
benefit.

I think most physicians, I think, would be talking about overall
survival benefits.

CHAIRPERSON NERENSTONE: Dr. George.

DR. GEORGE: A couple of points about some of the issues that have come
up. With respect to the curve models, I think it\'s worth pointing out
that just to be explicit, these models are not correct in the long run
with respect to cures, when you\'re talking about an endpoint being
survival and disease free survival.

As far as we know, nobody lives forever. So in the long run these curves
will come together. This has been pointed out.

So the models aren\'t correct and that\'s it. They\'re correct in a
shorter term. They\'re correct or useful, as George Bach said, that no
model is correct, but some are useful. This can be useful in the short
run, five to ten years it looks like, but it is an issue about what
happens later.

And I was a little surprised that we didn\'t know about those long term
people, the ones that \-- the long term deaths, if they\'re due to
melanoma or to just some of the competing risks of aging.

The second point is Dr. Brawley\'s point. This is a well known concept
of the number needed to treat, and what you do is you look at the
inverse of the absolute benefit, in this case ten percent, say, in terms
of the disease free survival, and that gives you a point estimate of the
number you would need to treat.

So it would be a ten for ten patients to treat for one patient
benefitting. However, you\'d have to worry about what\'s the confidence
interval in that, and that, the way I would do it is look at the meta
analysis to give you a best feel for how precise that estimate is, and
doing it that way, you get your numbers like somewhere between, you
know, maybe five and 100.

I don\'t know. I didn\'t do the math, but it\'s a straightforward thing
you can do. But the hard part is getting what that absolute benefit is.
And I think that is relevant though to the discussion of what patients
or individuals would like to know about how it might benefit them, and
we said absolute benefit.

We talked a lot, and I like it, relative risk and things, but it\'s the
absolute benefit that really, I think, people can understand.

CHAIRPERSON NERENSTONE: Dr. Vanderpool and then Dr. Nelson, and then
we\'re going to turn to the questions.

DR. VANDERPOOL: When you say turn to the question, is that when we\'re
going to deal with the issue of what our final commission is?

My only comment, I was just going to ask you that question. When are we
going to get away from interpreting the data, which obviously our
presentations primarily direct us to do the kind of clarification that
we\'ve been doing, but when are we going to get to the issues of the
commission, the last two sentences on our FDA report?

And so if we\'re going to turn to that soon, then I\'ll wait to comment
at that point, and please put me on the list.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: Since my comment was looking forward to the discussion of
what significance means, you can certainly read the question before I
comment.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BRAWLEY: I\'d just like to come back to this issue of cure, and
perhaps what we\'re struggling with in an analogy to breast cancer and
colon cancer, nodal relapse in both o those diseases is unusual. Whereas
it\'s much more common, as has been pointed out in melanoma.

In the 1684 study, most of the survival benefit was seen in patients who
were treated at the time of nodal relapse, and it may be that there\'s a
small beneficial effect of melanoma \-- I\'m sorry \-- of alpha
interferon that is useful when applied at nodal relapse or nodal
involvement, whether that be at time of presentation or at time of nodal
relapse.

So there may be a small treatment effect when applied in those
situations, which may explain the survival coming together in the later
study, because those patients when they did relapse, many of them, I
think relapsed nodally and then may have survived longer. So that may
explain some of the discrepancies we\'re seeing.

CHAIRPERSON NERENSTONE: To turn to the questions then \-- Mr. McDonough.

MR. McDONOUGH: I\'d like to just ask and make one or two comments here.
I\'ve been sitting, and I\'m getting overwhelmed with some of the
statistics.

One, I am a Stage III melanoma patient. I did take interferon. I was in
1690.

Two, between my going into 1690, from 1989 to 1992, I was in the
infamous observation group. That\'s a hell of a place to put somebody.
Observation means we\'re going to watch you and see if you get sick.
That\'s what it means to me, and I\'m sure it means the same to every
patient.

Number three, these discussions that take place between doctor and
patient, how long do you think they\'re listening to what you\'re
saying?

I\'m a public school teacher, and if we could get them three, three and
a half, four minutes of attention span, we were doing a job. Now, you
introduce fear. You introduce stress. You introduce feeling lousy. You
introduce lack of education on many of the people\'s parts that you\'re
talking to, and do you really think they\'re going to grasp in the five
minutes you have between this room and the guy that\'s sitting in the
next room?

And I don\'t castigate you at all. I\'m not saying that. What I\'m
saying to you is really how much time do you really have to deal with
this? It\'s a hard task.

As far as toxic, I took the high dose. Now, I just went \'89 to \'92 in
observation. Now I\'m presented with I may be in the observation again
or I might get low dose and I might get high dose. I prayed for high
dose. I was lucky. I got it.

How hard was it to tolerate? First week, very rugged because I didn\'t
realize what was going on, because I took it later in the day, and I
started to believe what they were telling me. Take your Tylenol, this
and that. I started to adjust to it.

Six months into the treatment, I was back playing senior softball. I was
traveling around the country with a little cooler with the drugs in it.
Nobody wanted to room with me. They thought I was a junkie.

Speaking of rooming with you, this room is cold. I\'m waiting for Rocky
Balboa to come in.

But getting back to the whole thing, the handling of the fever was
fairly easy to do. The handling of the malaise, I mean, I got my energy
levels back. I\'m certain some people are having a terrible time with
this drug. I\'m certain of it. But by the same token, I talked to a lot
of people around the country as a patient, consultant, counselor,
whatever you want to call me, through several different cancer groups,
and most of them come back with this particular point that bothers me,
and it bothers me a lot.

When you talk to your patient about your particular clinical trial as
opposed to interferon, do you talk to them about the other 101 that are
available, too, or do you just compare yours to interferon?

There\'s 103 clinical trials out there. What guy in this audience is
conversant with all 103? If you are, you are the man. And that\'s what
these people are faced with. That\'s what they come up with on the
phone. Should I take interferon or should I take this trial at
University X or University Y or University Z?

And me as just a survivor, an interested person trying to help, how do I
advise these people? I can\'t advise them. I do refer them to you people
many times, but it is a very confusing situation for a patient, very
confusing.

And I strongly urge you to take into account when any clinical trial is
designed this observation group. That\'s a terrible place to be.

Thank you.

DR. BRAWLEY: Can I ask Mr. McDonough a question? Is that allowed?

CHAIRPERSON NERENSTONE: Go ahead.

DR. BRAWLEY: Mr. McDonough, realize that we didn\'t know this
information when you went into the trial, and one of the reasons that we
now know this information is because you and heros like you went into
the trial.

But would you take interferon today if diagnosed today if it was
explained to you that for every 20 people we give interferon to 19 do
not benefit? They get all of the side effects, but none of the benefit
and one out of every 20 would benefit?

MR. McDONOUGH: Short answer, yes.

Long answer, from what I can gather here, I\'m hearing ten percent, 15
percent, five percent. I frequent Atlantic City not a lot, but now and
then.

(Laughter.)

MR. McDONOUGH: If I walk in and they tell me I\'ve got a 40 percent
chance on that table and I\'ve got a 50 percent over there, I\'m over
there.

If one of you gentlemen stand up here and say, \"I\'ve got the cure and
it\'s right over there,\" I\'ll be the first guy in line with my arm
out.

I know it\'s an insidious disease. I know it has a terrible toll. Why do
you think I\'m on this Committee? Financial gain? I\'m 70 years old.
I\'m on this Committee because if the real bullet comes down the line,
and it may be this bullet down at the end of the table here. It may very
well be. I don\'t know that. I don\'t know the Xes and Os like you
folks.

I\'m a coach. You want to talk about baseball, I can talk to you about
that, but honestly, yes, sir, I would take it again because I did the
observation. I did the not treatment deal, and I would never not treat
something again.

CHAIRPERSON NERENSTONE: Dr. Siegel.

DR. SIEGEL: Thank you.

I just want to make a comment or two to put in context the questions
we\'re asking and what we\'re asking and why, particularly in light of
some of the public comments from earlier this morning.

And I appreciated hearing the perspectives of all the public commenters,
and I think they\'re all important and I\'m sure sincere and valid and
useful perspectives.

But I want to provide some background to the notion presented by a
number of people that it was \-- well, different words were used \--
undemocratic, perhaps paternalistic, restricting people\'s choice,
undermining the informed consent process to state that a trial couldn\'t
be done provided that there was informed consent, and to say that the
framework in which medical research is conducted in the United States
and worldwide tells both at the ethics as well as law and regulations,
tells us otherwise.

There is, as I think everybody here knows, a raging debate about when
placebo controlled trials are \-- with full informed consent \-- are
acceptable where there is a proven effective therapy. Some have argued
in very prestigious medical journals never. Others, including many at
the FDA, have argued that that\'s the wrong place to draw the line, that
there are many therapies for symptomatic disease, transient benefits or
whatever that it\'s quite appropriate to as long as there\'s adequate
informed consent to do placebo controlled trials.

But there is a broad consensus and a broad, I believe, societal
consensus that somewhere there\'s a line, and I think that\'s really
what this is about as to where that line, where this treatment is
relative to that line; that at some point there are therapies whose
benefits, whether on irreversible morbidity, serious morbidity,
mortality, taken perhaps and probably appropriately in conjunction with
their harms and adverse effects, are such that it\'s inappropriate to do
a placebo controlled trial, even with full informed consent of the
patient.

Now, you can look into what is the reason or what is the logic behind
that. I\'m sure a part of it reflects as was noted, you know,
imperfections in the consent process. Part of it reflects, as some of
our commenters noted, maybe a lack of trust of the community fully in
medical researchers not to take advantage in certain settings.

I don\'t want to do a lot of speculation. We have ethical experts here
who I\'m sure can answer that question better than I can, but suffice to
say that there is rather broad agreement that there is a level beyond
which when there\'s a proven therapy it\'s inappropriate to do a placebo
controlled trial, and I can tell you that in the international community
and nationally, as the FDA has advocated for broader placebo controlled
trials, we\'ve often been severely criticized saying, you know, even
though they have full consent, people will say, well, this is, you know,
capitalistic exploitation of third world populations, you know, and how
can you offer people placebo when you know there\'s a proven therapy out
there, and how do we really know that they\'re being informed and this
trial is just unethical to do?

So it\'s important to know that at least from our perspective we\'re not
proposing something that undermines informed consent or that is on the
face of it just inappropriate to say you can\'t do this trial even with
informed consent, but rather to determine where against that spectrum,
an analogy that this trial and what we know about this drug falls are
its known benefits, and that\'s what the discussion has been about, and
I think that\'s very useful. Are the known benefits together with the
risks such that it is appropriate to ask people to consent not to get
this therapy, knowing the risk of consent, knowing people who consent to
be in trials often have undue expectations about the experimental
therapy?

Just to carry that one step further, that notion of what can or cannot
be consented to, although it\'s a slightly weaker analogy, there\'s also
a broad, supported by law, public expectation and regulation, consensus
that the FDA can and should stop clinical trials that we deem to be
unsafe.

There\'s not an expectation that, well, if we think it\'s unsafe as long
as you tell the patient all of the safety information and the patient
thinks it\'s safe enough, they can take that trial.

So the informed consent is underpinning our ethical basis. It\'s an
important part of clinical research, but there\'s a limitation to when a
trial with informed consent, even with informed consent, is appropriate,
and also there are issues that we may get to address about how to insure
that there is a good quality of informed consent.

CHAIRPERSON NERENSTONE: I think we should probably turn to the questions
and direct our discussion back to them specifically.

Just the paper that the committee was given, in the review of the
clinical development program for an investigational agent, FDA considers
the risk to human subjects. FDA may place on clinical hold a proposed or
ongoing investigation if it finds that \"human subjects are or would be
exposed to an unreasonable and significant risk of illness or injury.\"
Withholding an effective treatment may constitute an \"unreasonable and
significant risk\" for trial participants, depending on the known
benefits of the treatment and the consequences of withholding it.

Given that INTRON-A is an effective adjuvant treatment for high risk
melanoma, please discuss the following.

Well, I think the first question is \-- that\'s the whole crux of the
debate: is it an effective adjuvant treatment?

But the first question is: data regarding the efficacy of interferon ad
adjuvant therapy for melanoma has been summarized in detail. The
toxicity is well described. Of note, Schering estimates that
approximately 60 percent of patients with Stage III disease and 21
percent of those with Stage IIB disease in the U.S. currently receive
adjuvant therapy with INTRON-A.

Based on this information are patients who forego INTRON-A therapy to
enter a placebo controlled clinical trial exposed to unreasonable and
significant risk?

And then would the answer differ for patients with Stage IIB disease
versus those with Stage III disease?

I\'m going to take the chair\'s prerogative and comment a little bit
about what I think part of the problem is. With the weight of the
evidence, interferon is clearly not a home run, but I think it\'s a
beginning place. So I would be uncomfortable with a placebo controlled
trial in a large Phase 3 study, looking to advance the adjuvant
treatment of melanoma, of high risk melanoma, however you want to define
that patient population, especially if you\'re going to keep it in the
FDA wordage that interferon is already approved for.

The problem I see is really for those people who do not want to go on an
interferon or interferon controlled trial. I think you could get around
that by your informed consent, and I certainly appreciate Dr. Brawley\'s
concern that you are treating nine patients or ten patients and one
patient will have benefit maybe.

But I think it\'s very important for us to point out in the informed
consent for somebody who\'s going on a Phase 2 trial or a Phase 1 trial
that you may have to treat 100 patients with no benefit because these
are very, very experimental treatments, and I think investigator bias
and I think physician bias play a very important role here.

And I think when you extrapolate results that work in a mouse and say
this is our most promising vaccine and it has no toxicity, that\'s an
investigator bias that the patient wants to hear, and we have this drug
that really is very toxic and only, you know, one person out of ten is
going to benefit, but we have no data that any patient is going to
benefit from this new treatment, and I think that has got to be put into
the informed consent.

And patients have a right to know that no matter whether in University A
or University B or University C.

Other comments? Yeah, Dr. Vanderpool.

DR. VANDERPOOL: This is a complex issue in light of the FDA\'s
responsibilities to see that approved drugs are efficacious and also to
protect the public from unproven treatments. So in a sense, I can
empathize quite deeply into why the FDA has made this determination that
patients should not be allowed to enter Phase 2, not to speak of Phase
1, trials without first going through the standard approved therapy.

On the other hand, for the FDA or any other agency to keep patients from
entering clinical trials that have to have rationality, that have to
have the three requirements of the Belmont report, harm benefit
analysis, informed consent, and justice, but to keep patients from
entering any of those trials seems to me to go against the grain of
self-determination both in ethics and the U.S. law.

Persons have a right to refuse treatment. They have a right to decide
such matters on the basis of their own values.

The predominant value I\'ve heard all morning is that of extending life.
We\'ve talked some about the other value of pain and suffering. Some
patients would choose no pain and suffering over a lower continuity of
life.

And then there\'s the question of just hassle, having to go back and
forth and spend one\'s year in oncology clinics.

It seems to me the right of determination, self-determination, is a very
strong reason why this decision should be taken away. I mean the
decision would be reversed.

Also, the right to privacy. The right to privacy has to do with the
constitutional protections of physician-patient conversations and
decision making with the interference of others.

So it seems to me that both on ethical and constitutional grounds that
there are some strong reasons why this decision to keep patients from
being able to enter clinical trials even if they haven\'t taken
interferon as the approved therapy \-- their right to enter those trials
should be preserved.

Now, the question of informed consent, of course, comes into all of
those decisions, both informed consent within the physician\'s office,
informed consent within any clinical trial setting. So informed consent,
both the process and the document, would have to be full and thorough,
but I\'m talking about the more basic principles of what values patients
have for their decisions.

Obviously, Coach McDonough would go with extension of life over pain and
suffering. I suppose in his sports career he probably endured a good bit
of pain and suffering even, you know, just for the purposes of winning
the game. I did also.

But those of us who value extension of life over pain and suffering
should recognize that other people have different values and they ought
to be able to operate off the base of self-determination with those
values in mind.

CHAIRPERSON NERENSTONE: Dr. Kelson.

DR. KELSON: First of all, we\'re discussing melanoma. This obviously has
implications for many other diseases. It\'s a very good paradigm though.

As I read Question 1, I think that you\'re \-- correct me if I\'m wrong
\-- you\'re really focusing on a Phase 3 trial when you talk about a
placebo controlled arm or at least that\'s the point I would like to
address in this, and it seems that much of the discussion here is what
would be the comparator arm in a future adjuvant trial, and are patients
compelled to accept a randomization to receive interferon high dose or
an experimental arm, or is it, as we heard a lot this morning \-- could
one imagine a study in which there would be an observation or placebo
controlled observation?

DR. SIEGEL: Just for clarification, regardless of which question one
addresses, we\'re being faced with a spectrum of questions, and we\'re
interested in input on all of them, both for a drug which already has
been shown to be promising, is it appropriate to compare it to placebo,
but also for folks with less data where you know very little . Is it
appropriate just to withhold interferon and do an open label?

DR. KELSON: Right, and I think Stacy alluded to this. The issue that
struck me at least in this particular disease is is it so compellingly
efficacious that a patient would be put to an unreasonable risk by not
receiving that therapy and, therefore, we should say, \"Listen. I don\'t
care how you feel about this. It\'s just not in your best interest to
not receive this drug\"?

I\'m struck again by the meta analysis in which, since this is curative
therapy if it\'s adjuvant, the upper limits of the 95 percent confidence
tightly draw across one. I\'m not compelled that there\'s overwhelming
evidence that this is a clearly efficacious therapy.

And that strikes me a great deal when you talk about unreasonable and
significant risks of withholding treatment. That would make me much more
sympathetic to the problem of forcing a patient to receive interferon.

And lastly, I am struck by the fact that although it is an approved
agent, if we turn the number slightly, 40 percent of Stage III patients
are not being treated, and 80 percent of Stage II patients are not being
treated with the approved therapy, and therefore, clearly not everyone
has been convinced that this is putting these patients to an
unreasonable risk.

CHAIRPERSON NERENSTONE: Just a point of information about that, Dr.
Kelson. I think that those of us who are in the world of treating
patients, if you look at the ECOG studies, there were very clearly and
carefully screened patients who were performance status zero and one,
and we have lots and lots of patients who are not performance status
zero and one and who, therefore, many of us feel wouldn\'t even be
candidates for interferon.

So I think interpreting those numbers are fraught with difficulty as to
what they really mean about the acceptance or not acceptance of the
treatment.

DR. KELSON: Right. Also being in the world of treating patients, as a
card carrying member, since this is adjuvant therapy, I suspect, and
these are melanoma patients who have had the primary resected, I mean,
we also face older patients who have had resections for colo-rectal
cancer, but I would suspect that a pretty substantial hunk of that 80
percent who are turning it down are relatively fit people who ordinarily
would be treated. They don\'t have advanced disease.

DR. SIEGEL: It\'s worth noting that there are probably a lot of
weaknesses to those data. Another one, for example, is that we also
believe that there are, but we don\'t know numbers, but we understand
that there are some patients being treated off label with other
interferons that are similar in activity but not approved for this
indication.

That said, we felt, and I think your responses reflect that, that this
information was relevant to how people are weighing the data and this
indication and what choices people are making.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: I\'d like to comment on the unreasonable and significant
issue and try to place it actually in the context of the international
debate that you referred to. What strikes me about that language, which
is the first time I\'ve really looked at it closely, though I\'ve
probably read it often, is it needs to be both unreasonable and
significant, and I think we would all agree that the risks we\'re
discussing are significant. So the question really comes down to whether
it\'s unreasonable to decide not to have high dose interferon therapy
and, by extension to have a control group that does not include that as
part of that treatment.

I mean the Declaration of Helsinki in Paragraph 29 talks about proven.
That\'s the language that\'s used there. What strikes me as problematic
with often people\'s understanding of what proven means is that they
don\'t appreciate that safe and effective means safe enough and better
than what we tested it against.

As a culture we tend to think safe and unsafe and effective and
ineffective, which turns into a categorical variable that really is a
continuous variable.

So what strikes me in this entire discussion is that equipoise \-- I
mean, the uncertainty about the decision to do this rests at two levels.
One is the professional level of the statistical determination, which is
in debate, but even if you say, yes, we agree that you have a ten
percent difference or we agree that you have a ten month extension in
expectancy of life if you\'re not going to be cured, we can still then
debate the reasonableness of that tradeoff. There\'s still uncertainty
about that decision. So equipoise is existing at both levels.

The other document that\'s part of the debate is ICHE-10 choice of
control group, and in that document basically you can allow for \-- and
I\'d like to have other language suggested about observation and
placebo. It would be great to have another term, but basically even if
proven treatment exists, you can have that if one of two conditions
exist, and there\'s some uneasy tension between them: so-called assay
sensitivity, which I notice is the third question coming up. Can you
really tell in the trial whether it\'s effective? The question raised
about the vaccine trial earlier against high dose interferon.

The other is informed consent if there\'s no serious morbidity or
mortality. So the difficulty there is that informed consent is tied to
the lack f the seriousness of the outcome of withholding, in which case,
you know, it may or may not apply here, but in E-10, I think it\'s
assumed that equipoise exists. That\'s the difference. It assumes that
we accept that it\'s safe and effective, and we\'re willing to withhold
it if, in fact, the disease is not serious, doesn\'t have serious
morbidity or mortality as a result of that.

So in this case the approach I would take, which really does go towards
informed consent to some extent, but I wouldn\'t rely on it entirely, is
that it doesn\'t strike me either within the expert community, in
listening to the experts here, or within the community of patients who
would be the ones going into these trials, that, I mean, there\'s
sufficient uncertainty in my mind at least listening to it to where I
wouldn\'t necessarily apply the choice of control group, E-10, to that,
but would really analyze whether uncertainty still exists, maybe not in
some minds, but at least within enough of the expert community to where
not having high dose interferon, even though it\'s, quote, proven safe
and effective, is an appropriate position to take.

CHAIRPERSON NERENSTONE: Dr. Pelusi, can you hear us? Dr. Pelusi, can you
hear us?

(No response.)

CHAIRPERSON NERENSTONE: Dr. Redman.

DR. REDMAN: Dr. Siegel said he was open for all comments. So I\'m going
to avoid the Phase 3 and come back to it in a minute, but you know, I
mean, there\'s a great discussion among the experts in melanoma of what
control groups should be, and I\'m not surprised patients are confused.

I get the sense that one of the restrictions being looked at is to imply
or impose on patients that decline receiving interferon not being able
to participate on a Phase 2, single arm study that is trying to ask a
basic either clinical or laboratory question regarding the disease and
treatment.

Most consent forms do have unknown benefit clauses in them. At least
most are required to have that for a drug. You know, until we have a
national informed consent policy, which probably won\'t happen, but, I
mean, until we do, everybody\'s consent is going to be different.

And Dr. Slingluff had a suggestion that may overcome that, and I\'ll
just leave it at that, but I am definitely, as a physician who treats
predominantly melanoma, greatly against restricting somebody from being
able to participate in a Phase 2 single arm study because they\'ve
declined interferon.

Regarding a control arm for Phase 3, I think that\'s between, you know,
industry or the holder of the IND and the FDA, hopefully will come to
the FDA at the end of Phase 2 and say, \"We want to do this trial,\" and
at that point in time determine is interferon an adequate control arm.

I think if they\'re going to product license application in that regard,
I think it is the FDA \-- and I know you\'re asking for our opinion.
I\'m not sure I know the answer to that question of whether that should
be construed as the standard, but as far as Phase 1 or Phase 2 single
arm studies at single institutions or even sometimes multi-institutions,
I think those trials should be available to patients who decline
interferon because I imagine a lot of physicians would decline
interferon.

So I don\'t think imposing that will on the patients is appropriate.

CHAIRPERSON NERENSTONE: Dr. Przepiorka.

DR. PRZEPIORKA: Thank you.

I had the pleasure of participating in a discussion over the weekend
regarding the imposition of benevolence over autonomy, and living
unrelated donors of stem cells and whether or not it would be ethically
appropriate to go back and ask them to donate once again since the
procedure has substantial toxicities, a risk of mortality, and
absolutely no benefit whatsoever to the donor.

And after a minimum of just 15 minutes of heated discussion, it was
concluded that we as physicians do care for our donors, but if they
really want to do this, we should not deny them the opportunity as long
as they pass the psycho-social review and we\'re sure they\'re not
crazy.

(Laughter.)

DR. PRZEPIORKA: And I think if any patient would look at the data that
we saw today, they would say there was a substantial risk of toxicities
with interferon, and as far as I can tell, there is no proven benefit
with regard to survival that I think would entice a patient to take this
if there was something else available.

And I think that\'s the key. So if one uses the acid test of did we
really improve survival with this drug and to say that then this should
be the standard of care and the comparator arm in every future trial, I
would have to say no.

But I\'m a firm believer in looking at relapse free survival, as well,
since we now have all sorts of ways to keep our patients alive, and
certainly they would prefer to be alive without disease rather than with
disease, even if they end up dying at the same time point.

And clearly relapse free survival is significantly improved,
statistically significantly improved with interferon, but I\'m not
certain I would conclude that it\'s clinically significantly improved if
there is something else available either.

So I would not have any hesitancy in saying yes to a placebo controlled
trial for this group of patients with melanoma, with the caveats that
they are appropriately consented, and there is a safety monitoring board
watching this closely.

And I\'m a Baysian kind of person rather an intention to treat kind of
person. So I like to see a trial that\'s as small as possible as well as
monitored closely.

That\'s not to say that I would actually do this for every drug under
any situation. I think this is a specific situation where we really
don\'t have statistical significance and improvement in survival, and
the relapse free survival is there, but not a whole huge amount, and
that would be the only other caveat I would add to this.

CHAIRPERSON NERENSTONE: Dr. George.

DR. GEORGE: I have a couple of comments. One is I\'d like to make
something explicit that may have been implicit. We\'re talking about
melanoma, but I think maybe the FDA is worried about the slippery slope
issue, that is, having this be, decisions that are made in this case be
used as precedent for this in this situation.

There is, as we heard, a huge and growing number of INDs that are a lot
more in line, I think, with the biologics and the biologically targeted
agents, but to me this doesn\'t bother me because there is a \-- FDA
made a judgment call in this case with respect to unreasonable and
significant risk. This was on this particular case.

Some of us might disagree with that. A lot of us do, apparently, but
it\'s an individual case, and I don\'t think it sets the precedent.

The corollary to the above and something I\'d like to also mention that
I don\'t think has been brought up is that we all want better therapies,
and we want them seen. And one barrier to that is the number of patients
that enter on clinical trials. This is notoriously low in cancer, and so
anything that stands in the way of that that is not absolutely
essential, I think, should be removed.

I think we need to encourage people to enter trials.

CHAIRPERSON NERENSTONE: Dr. Siegel.

DR. SIEGEL: Yeah, thank you.

Just a quick comment about both that issue, the issue of developing new
drugs and treatments, as well as on a couple of comments.

There have been some comments, and I don\'t think anybody misunderstands
this issue, but there have been a number of comments to be suggesting
that our policy had mandated interferon therapy or denied patients the
right to refuse interferon therapy, and I\'m sure \-- I hope everybody
on the panel and everyone in the audience appreciates that what we\'re
talking about is not \-- of course patients have the right to decide
whether or not they want to get interferon. The issue is who\'s enrolled
in clinical trials.

And I assume that the comments from Dr. Vanderpool on self-determination
were not addressed specifically to self-determination in terms of a
choice to take interferon, but the implications of that on one\'s access
to clinical trials.

But saying that, so I would just turn it around and say the question
we\'re asking is if you\'re doing \-- well, let\'s put it now in terms
of Phase 1 or 2 of a clinical trial in a vaccine in which you\'re
looking to see if you get antibody responses. You have an option of
studying that in people who have a low stage lymphoma, a low stage
melanoma, grade melanoma for whom interferon hasn\'t been proven to be a
benefit, and you have an option of studying that in patients who are
also getting interferon and looking at its toxicities and its antibody
response in patients who are getting interferon.

Those are not perfect options, and some people don\'t like that option,
and so the question in that setting boils down to: is it an appropriate
alternative?

So those I don\'t think would not get developed. The question is: is it
an appropriate alternative option for a sponsor and investigator to go
to a patient and say, \"I have an experimental therapy. Here\'s a
consent form,\" and the consent form, of course, describes that I don\'t
know whether it works or not, \"and you\'re eligible to get this
experimental therapy provided you refuse interferon therapy, and here\'s
the risks and benefits of interferon therapy\"?

Suffice to say that that raises important questions. Those are the
questions we\'re asking the Committee to help us think through.

CHAIRPERSON NERENSTONE: Dr. Sledge.

DR. SLEDGE: I don\'t know if I\'m a Baysian sort of guy or not, but I do
think statistical issues actually are fairly central to this discussion.

When I look at this data set and compare it to other adjuvant data sets,
what I\'m struck by is the tiny number of patients who have gone onto
these trials.

For instance, by comparison six, eight weeks ago in San Antonio there
was a 9,000 patient adjuvant breast trial that was presented whereas we
have what, seven trials here that have a total of 3,700 patients?

A large part of the argument that I\'ve heard today surrounds what
represents clinical benefit for adjuvant therapy of melanoma. The data
that I see are pretty compelling for relapse free survival. I don\'t
think there\'s any serious question about that from a statistical issue.

The overall survival data I think are more questionable. I mean, I think
we\'re talking about fairly modest differences with confidence intervals
that either approach or cross unity, and I think given that relatively
modest survival differences, given the real toxicities, I think there\'s
a legitimate question to ask whether or not high dose interferon should
represent standard of care in this setting.

And based on that, I don\'t think it\'s currently appropriate to mandate
it because I don\'t think we have compelling evidence for a survival
advantage.

Now, I also say that these things change. You know, if you look at
overview analyses in breast cancer and adjuvant trials over time, there
have been real shifts in our interpretation of the data both in terms of
relapse free and overall survival data both for adjuvant chemotherapy
and for adjuvant hormonal therapy over time as more data has come in and
as more trials have come along.

So what may not be striking and impressive and representing, you know,
whatever the current equipoise is today may well change two years from
now, five years from now as more data comes along.

So I\'d say, you know, specifically on this issue talking about today\'s
data set, I mean, my bias is that we don\'t yet have sufficiently
compelling data that we should require this, though it certainly could
change a few years from now.

CHAIRPERSON NERENSTONE: Dr. Fleming.

DR. FLEMING: Let me begin by acknowledging that the informed consent
process is really critical to the ethics and integrity of clinical
research. Having acknowledged that, Mr. McDonough\'s comments, I think,
bring to mind again the reality though that it\'s not perfect, and it\'s
my sense then that there certainly can be interventions that have such
substantial benefit to risk evidence that I think withholding effective
treatment could constitute an unreasonable and significant risk.

So I think there are settings in which the FDA could appropriately judge
that there should be a restriction in the design of clinical trials and
what the control regimen would need to be. Simply having acknowledged
that we have an approved intervention though I don\'t think is
necessarily stating that we have that level of evidence. It\'s stating
that we have done adequately controlled trials to establish efficacy and
safety such that we have a favorable benefit to risk profile that
warrants making these products available and allowing people the
opportunity to choose to use them.

So where are we? Jay Siegel talks about the line. Where are we in this
specific setting? What is the strength of evidence?

As we look at the 1684 trial and we look at recurrence free survival and
the cure rate analysis and we\'re saying in that analysis there\'s a 12
percent increase in the estimated cure rate, if, in fact, that
translated into a long term survival benefit of ten to 12 percent,
we\'re talking about something on the order of a 30 percent reduction in
the failure rate.

And if we\'re talking about that kind of survival effect, particularly
with a very tolerable regimen, if my own opinion were being solicited, I
would say that could readily be interpreted to be across the line such
that one would need to protect patients against being asked to go on
clinical trials that wouldn\'t offer them that level of benefit.

My concern is trying to understand what these data really tell us
reliably about effects on what I would particularly care about, which is
the survival effects. The survival effects that we apparently are seeing
here are much more modest in magnitude than what might have been
suggested by the cure rate analysis of 1684, effects that are relative
risks, ten percent reductions, absolute reductions, three to five
percent, with some uncertainties as to whether that truly is the long
term benefit and whether that\'s, in fact, established benefit.

That\'s the point estimate, and as Dr. Sledge has just pointed out, this
is, even though a substantial aggregation of data, it\'s still not
sufficiently substantial when we\'re trying to nail down differences on
the order of ten percent.

There has been a lot of discussion as well that there are substantial
toxicities associated with achieving this level of benefit. So this is,
to my way of thinking, Jay, this is why this is such a difficult issue.
I think there are definitely settings in which the benefit to risk
evidence is so strong that it would be appropriate to restrict access to
clinical trials that would require those trials would provide access to
those interventions.

The nature of the evidence we have about survival here is sufficiently
uncertain and what we do have is suggesting a relatively modest benefit
in the context of what is a substantial amount of toxicity that\'s
required to achieve that benefit.

Hence, this is why it seems to me that it\'s very appropriate to suggest
that whereas the ideal would be to inform participants of the benefit
and risks of interferon, encouraging designs of trials that can build on
interferon to at least acknowledge that there could readily be
substantial participants who would choose not to enter into a trial that
would require them to receive interferon.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: Yes, I agree that looking at the totality of the data that
we saw this morning that requiring patients with either Stage II and
probably with Stage III interferon, Stage III melanoma to enter a trial
that randomized to interferon is not something that you should do. I
think that society, to take Coach McDonough\'s analogy a little further,
society does put a fence around who can enter an Atlantic City casino.
We don\'t allow minors, and there\'s pressure not to have people spend
the rent money at those casinos.

But once you have those fences, I think the line of entering patients
with melanoma with either Stage II or Stage III, to enter them in a
placebo controlled trial, for my view, should be okay.

Basically if we\'re worried about setting a precedent on data that was
evaluated seven years ago, this is a moving field, and I don\'t think
that we should be compelled to look at that as a gold standard or
something we can\'t back away from because times do change. We are seven
years down the road, and I think it is reasonable to allow a trial
design that does not include an interferon arm.

CHAIRPERSON NERENSTONE: Dr. Vanderpool.

DR. VANDERPOOL: Dr. Siegel, you can be sure that when I referred to
self-determination I didn\'t imply at all that self-determination only
applied to patients making decisions in the clinic, but to other areas.

I agree with the last three speakers, Sledge, Fleming and Blayney, on
how there doesn\'t seem to be a compelling case for forbidding patients
from entering other clinical trials before they take interferon given
the data about interferon.

At the same time, I would argue from an ethics and legal perspective
that even if the data were much stronger, that patients in consultation
with their physicians do have a right to say, \"No, I don\'t want that
standard treatment,\" and they should have the right to enter a Phase 2
trial under a variety of circumstances.

Now, does that, Jay, take power away from the FDA? No, I don\'t think it
does. The FDA has a right to decide which drugs to approve. It has a
right and responsibility to decide which clinical trials for new drugs
can go forward. You don\'t want an untried drug in a Phase 3 trial, et
cetera.

So you can determine what the trials are. You can determine what the
drugs to approve are, and you can protect the public vis-a-vis
clinicians not using unproved remedies in clinical practice. All those
are under the purview of the FDA.

I think the only problem I have here is the FDA stepping into the realm
of determining what patients should decide with those things that are
already approved, clinical trials, on the one hand, and therapeutic
measures on the other.

So I think the FDA has overstepped its bounds on this, but it doesn\'t
mean that it doesn\'t have and shouldn\'t continue to have the vested
authorities that it has with respect to approval of drugs, approval of
different kinds of clinical trials and protecting the public\'s health.

DR. SIEGEL: Let me just get a clarification, but first, I want to assure
everybody here that (a) this is not about our concern about what power
we have; just our concern about how best to delegate and carry out the
responsibilities that we do have, although, if I understand your
question \-- well, let me get some clarification on that.

But also I want to reassure Dr. George that our question here really
isn\'t, although I appreciate your thinking about that, one of a
slippery slope. It really is an issue of what\'s the right thing to do
in melanoma. This is something where we\'re particularly troubled about,
and we\'re getting some very useful advice in that regard.

I think as you all know or as you heard today, we did not make this
decision based on the rather compelling evidence on disease free
survival. It was only as more evidence of survival accumulated we made
that decision.

We\'re here because we want the feedback we\'re getting on that
decision.

Dr. Vanderpool, let me ask you this, and this does go to our
authorities. It sounds like from what you\'re saying that you\'re
carrying this to an extreme, which would be very different from what
we\'re hearing in other circles, that there would be no case in which
the FDA should say patients can\'t with consent forego a therapy even if
proven life saving and very well tolerated.

Are you suggesting that that is not an appropriate use of our authority,
that we\'re not supposed to review trials to determine that?

DR. VANDERPOOL: That\'s a tough one. I think the devils are in the
detail of the particular circumstances you would have, but I think I can
think of a variety of circumstances where patients would not want to
take a certain drug regimen based on worries over quality of life and so
on, but should have the right to enter clinical trials with drugs that
were wanting to treat that condition that have not yet been approved.

This is a new problem in biomedical ethics that I discovered as I was
reviewing these materials. So I certainly would need to think about the
issues further, but generally, I think the patient\'s rights do trump,
although the FDA has the authority, as you say, not just for power
reasons, but for the protection of the public, to decide which trials
are available.

But my worry is other FDA\'s reaching further and deciding what patients
have to have decided to have done before they can enter those trials.

DR. SIEGEL: Well, let me just say from a philosophical point of view \--
and Dr. Rosenberg raised this issue \-- that I was involved in both of
these decisions, and the FDA determined within actually the space of a
year or so and on the same database, both that Interleukin-2 should be
approved for renal cell carcinoma because it was quite reasonable for
many patients to elect that the demonstrated benefits outweighed the
substantial risks and side effects.

And at the same time we did allow, I think, within a year of that the
onset of a placebo controlled trial of interferon gamma in the same
population base provided those patients were told of the risks and
benefits and chose not to get interferon, based on the fact that we also
felt it was very reasonable for patients and the physicians to decide
otherwise.

And I couldn\'t agree more with the notion that patients and physicians
should have those choices.

On the other hand, I have to tell you the agency has been roundly
criticized in many areas for allowing placebo controlled trials with new
drugs where there are proven therapies out there, and I think our rather
broad understanding with the agency is that there\'s a gray zone that
this is in probably, but that somewhere there is this line.

And it would be interesting at some future point to have other
discussions about whether there should be such a line, but I can assure
you that in practice there is such a line, and that there is a broad
expectation in many circles that we do draw such a line; that there
comes a point that there are therapies out there that are cured of live,
prolonging life saving, well tolerated therapies out there that we will
not allow a sponsor who has got an experimental therapy to say, \"Look.
Here is this proven therapy, but if you\'ll agree, you can get this
experimental one or placebo,\" or something like that.

So it\'s not \-- you know, it\'s not been that black and white. It\'s
not been that that\'s outside our purview. At least that\'s not the way
it\'s been viewed in much of the patient advocacy community, much of the
international community, and within the agency, as well.

CHAIRPERSON NERENSTONE: Dr. Albain.

DR. ALBAIN: I\'m struggling a big going back and forth as we\'ve been
doing in our discussion between Phase 2 and Phase 3 here. And I was
struck with all of the advocacy letters and E-mails that we got that
really they were addressing the issue of Phase 2 trials in probably over
95 percent of those.

And that being said, if we could be fully convinced that the consent
would be informed about a Phase 2 trial, I\'m left with what exactly are
the endpoints of a Phase 2 adjuvant trial, and in fact, at least in
breast cancer, you know, you really can\'t do a Phase 2 adjuvant trial.
You can try if you were certain you had a good, intermediate biologic
endpoint, a surrogate, such as, perhaps in the neoadjuvant settings for
pathologic CR.

But I would have to defer to the melanoma experts here today. Are you
fully convinced that in a small Phase 2 trial with a vaccine or other
biologic therapy that you can come up with a surrogate that would then
allow you to be excited enough to take that particular approach into a
Phase 3 trial?

And if you are, then in that Phase 3 trial, ideally you don\'t want to
be confounded by the presence of another biologic, I suspect. You don\'t
want to be confounded by interferon being on board in high doses when
you\'re testing another novel biologic.

So then you argue back around to the placebo, and then will you, in
fact, get a patient to accrue to such a Phase 3 trial when they have to
go onto an observation arm?

So then you\'re back again at square one, and I think a lot depends on
the experts here in melanoma biology and what can you do with smaller
sample sizes in a Phase 2 setting.

CHAIRPERSON NERENSTONE: Dr. Taylor. Oh, okay. Go ahead.

DR. SPITLER: Is this microphone one? Oh, it\'s on.

That was a great question, and I\'d like \--

CHAIRPERSON NERENSTONE: Please identify yourself for the record.

DR. SPITLER: I beg your pardon?

CHAIRPERSON NERENSTONE: Identify yourself for the record.

DR. SPITLER: I\'m Dr. Lynn Spitler.

I can give you a specific example where that has occurred, and it\'s a
study that I did of GMCSF as adjuvant therapy for a Stage 3 and 4
melanoma. At the time I went to Immunex in 1993 there was only
preclinical data that GMCSF would activate macrophages, and activated
macrophages would kill tumor cells.

Now, you wouldn\'t go to a prospective randomized Phase 3 trial with
that without getting some idea would there be clinical benefit, and I
proposed to them a Phase 2 trial, and they accepted it.

We treated 48 patients and compared survival with matched historic
controls from the University of Alabama database. Not great, you know,
but the best \-- it wasn\'t a prospective randomized trial. We were just
getting an idea would there be some clinical benefit that would warrant
doing a prospective randomized Phase 3 trial.

Well, that data were sufficient, which we published a year and a half
ago in the JCO, were sufficiently compelling that ECOG accepted that
data and did launch a Phase 3 prospective randomized trial comparing
GMCSF with placebo, and there\'s some vaccine arms in there as well.

So in that circumstance, the Phase 2 was sufficient to get to the Phase
3.

DR. ALBAIN: Given now that your new staging system shows such an
exquisite differential with very minor variations in these prognostic
factors, I think if you would have to, if you were to design such a
small Phase 2 trial, be very rigorous in who went into it.

And thus, you would then be exclusionary in that way. Because if you\'re
using historical controls, you can\'t use it the way we used to five or
ten years ago now that you have your new system that\'s much more
refined.

DR. SPITLER: If you apply the new system, the new system is wonderful
because it very specifically identifies prognostic indicators, and if
you match patients in the historic data base according to those very
important prognostic indicators, including the ulceration, including the
number of nodes positive, including whether it\'s microscopic or
macroscopic disease, you can match the patient populations, and I think
that that gives you a reasonable approach to suggestions of efficacy.

In our current study we used the AJCC database, which was the same one
that was validated with the new staging system, 17,000 patients, and
matched 1,000 patients from that database with 50 patients in our study.

DR. ALBAIN: Could I just follow up?

If this is kosher, Madame Chair, could I hear from one of the other
experts here, Dr. Rosenberg, Chapman, Schuchter, any of you over there,
what you think about this issue of confounding on Phase 3 trial if you
have another biologic on board, and are you concerned about missing
benefit to one of your new approaches?

I know ECOG has obviously struggled with this, and they\'ve chosen to
build onto the control arms, interferon alone.

DR. CHAPMAN: In fact, I\'d like to also mention that there\'s another
paradigm for a Phase 2 trial.

CHAIRPERSON NERENSTONE: Please identify yourself for the record.

DR. CHAPMAN: I\'m Dr. Paul Chapman from Sloan Kettering Cancer Center.

There\'s another paradigm that we use actually even more commonly for
Phase 2 trials that are one sided, that is, where we use a surrogate
endpoint of an immunological response, and we use that sort of as an
endpoint to determine whether to carry that vaccine forward.

That\'s I think even the more common scenario between our trials and
Steve\'s trials and a lot of other people\'s trials.

And that\'s an example where a Phase 2 can really direct you as to where
you\'re going to go.

In terms of having an interferon board, I think we have very little
data, except for the ECOG 2696 trial that we did with ECOG, which showed
that the high dose interferon, when given with the GMK did not appear to
affect or inhibit or deter the immune response to the GM-2 gangliocyte.

But you\'re right. I think many of us would be a little hesitant to go
forward with the Phase 3 without a least a little pilot data for the
individual live vaccine that we were looking at.

CHAIRPERSON NERENSTONE: Dr. Taylor.

DR. TAYLOR: I think that one of the things that hasn\'t been mentioned,
and it\'s truly why I think we have bioethicists is that to complicate
things is that although you go into the casino with your clothes on and
your ego intact and you\'re not sick, as a group of patients who have
melanoma, you\'re a vulnerable population.

As you alluded to earlier, you may not feel well. You\'re also very
frightened, and it\'s in that setting plus the setting that I see
physician researchers who are very biased and very excited about their
new study, that I feel that the FDA has to maintain that role as the
policeman for us.

Now, in this setting, I don\'t think the data is adequate to say that
interferon is the home run, and I\'m not willing to say that everybody
has to have it.

But I do think we have to keep the FDA looking at those type of issues
because we are dealing with vulnerable populations, and we are dealing
with excited doctors.

CHAIRPERSON NERENSTONE: Dr. Brawley.

DR. BRAWLEY: Dr. Taylor\'s comments are well taken. I don\'t treat
patients with melanoma. So I\'m not, I guess, your definition of an
expert on this issue.

I will tell you that the FDA in terms of proven versus experimental
therapy, I was thinking about in testes cancer where the FDA approved
therapies can cure 70, 80 percent of folks. It would be shame if those
individuals were allowed to forego what is a really high likelihood of
cure in order to go onto an experimental therapy because I really don\'t
think that the patient very frequently \-- and I\'m not one to baby
patients or government taking care of patients, but I fear the
investigator selling his investigational drug in that example.

I think one of the things that we have to bring forth here is that one
of the reasons why we have so many questions in melanoma is only about
three percent of melanoma patients have gone onto clinical trials over
the last ten years.

If we\'re going to move forth melanoma therapy, we have to increase the
number of people going onto those clinical trials.

Now, in terms of INTRON-A for melanoma, and again, I speak as not an
expert, and indeed, I\'m probably one of the least likely people in this
room to get this disease, but I honestly think that I would forego
interferon.

Coach McDonough, I don\'t gamble when I got to Atlanta, but I really do
think I would forego interferon A as being just not likely to give me
much benefit at all, and in that sense I think it would be fine that
individuals who felt like me could be randomized to trials that included
a placebo, especially since we\'re talking about so many people get
interferon who wouldn\'t benefit to begin with.

Now, is a placebo control trial ethical in any of these stages? I think
the answer is yes.

Is it unreasonable in any of these stages? I don\'t think it\'s
unreasonable at all. Indeed, as I just said, I think interferon therapy
may be unreasonable for some people, but again, I would defend folks\'
right to get interferon therapy if they wanted it.

Is a placebo control trial wise? In some instances the answer is it may
be very reasonable and very ethical, but not necessarily very wise in
terms of recruiting people in clinical trials.

I\'ll conclude by saying I, like Dr. Sledge, have difficulty with saying
that interferon currently is the standard of care. I think it is a care
option, but not necessarily the standard of care.

CHAIRPERSON NERENSTONE: Dr. Carpenter.

DR. CARPENTER: I just want to second what Dr. Brawley said and my
comments are very similar. We have \-- you can envision breast cancer
with a hormonal therapy where it would probably be not reasonable to
suggest that somebody forego some kind of first line hormonal therapy as
an adjuvant to taking unproven treatment as just not being in that
person\'s best interest, much like the testes cancer.

This just seems at the other edge of the slope. While there is a
therapy, there\'s at least a log of discussion among fairly
knowledgeable people about just how compelling the evidence is for it,
and given that uncertainty or the softness of that endpoint, then I
think more choice is appropriate.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: A couple of quick comments. I would modulate the emphasis on
self-determination a little bit, and I think it\'s an important
distinction to make between Phase 2 and Phase 3. Certainly many of the
arguments do appear to be presented as sort of the choice against
interferon in favor of some other therapy, which would be the case in a
Phase 2 uncontrolled fashion.

But when you move into Phase 3 efficacy trials, in effect, the choice
then is to enter the trial, and you\'re taking your, quote, risks about
which arm you may end up being randomized to.

So the complexity of the relationship between choice and the clinical
trials, I think, would have to be a much more nuanced discussion about
the justifications of choice.

I think a challenge to statisticians that would be interesting to see
how well it could be tackled is the extent to which you could
incorporate choices within trials that wouldn\'t undercut randomization
in a way that you could still make inferences.

But that goes way beyond my expertise in analyzing dropouts and
crossovers and all of that kind of effort, but that would be a worthy
kind of direction to move toward in the future.

CHAIRPERSON NERENSTONE: Does FDA sort of have a feeling of \-- okay.

DR. SIEGEL: You\'ve not only answered Question 1, but Question 2 as
well, except perhaps for the last sentence in it. So maybe that would
help move along. If you look at the last paragraph, should this further
be expanded?

The question asks if those patients who are allowed to go into protocols
using placebo or unproven adjuvant therapy should be expanded to include
those who refuse to receive interferon therapy. We have certainly
received a great deal of comment on that, although the last part of that
question would be one if there are additional comments, that would be
helpful.

If so, should any particular steps beyond IRB and FDA review of informed
consent documents be taken to insure that the patient has made an
informed decision?

CHAIRPERSON NERENSTONE: Dr. Redman.

DR. REDMAN: Regarding that last point again, going back to Dr.
Slingluff\'s, I am one who spends 20 to 30 minutes in a room talking to
a patient about adjuvant interferon, and we make our own material that
we give them even in a non-study situation.

I think it would be extremely helpful if there was some \-- I\'m not for
government regulation, but if there was some standardized summary of
information that uniformly we can give patients that they could do as we
do in breast cancer regarding different surgical options, that they
actually sign saying that they\'ve read this material, and it would be
supplementary to IRB approval of Phase 2 trials. did the patient sign
the interferon consent form or such?

We\'re still going to talk to our patients, and that\'s never going to
end. And then we\'re going to have different biases as physicians, and
we always will have those biases, but at least it levels the field
somewhat so that you\'re sure at least the patient did get some
information on interferon before being considered for an investigational
therapy.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: I would suggest if you\'re concerned about the quality of
the informed consent that you\'re going to have to move beyond simply
reviewing the documents. I don\'t have an answer about what that beyond
might be, but the whole issue of trying to measure and actually insure
adequate voluntary and informed consent is one that I think should be
tackled.

There are creative ways in more high risk, visible activities, such as
the artificial heart trial where consent, sort of patient advocate
people have been involved as well.

I\'m not sure that this would reach that sort of threshold, but I think
you should do something more than just look at documents.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: Yes, as someone who working through ASCO and others has
helped to get payment for clinical trials, I think that is also a
mechanism. To use Dr. Taylor\'s term, we have a lot of excited
investigators in this field, and perhaps if informing the patients of
whether Medicare, to take an example, will cover their clinical trial
and their specific features in the law as to whether Medicare will cover
that trial, that may be a useful check on some of the entry criteria.

CHAIRPERSON NERENSTONE: Dr. Siegel, do you want us to go to the end of
Question 3 or have we discussed this to your satisfaction?

DR. SIEGEL: Well, are there other comments on that or those are all of
the comments on this questions? If so, that\'s fine. If not, we\'d
certainly welcome others.

As far as current Medicare policy, I believe if it\'s under IND at FDA,
it\'s automatically covered. So that\'s one of the \-- I was involved in
that policy, and I believe that\'s one of the conditions.

CHAIRPERSON NERENSTONE: Dr. Przepiorka.

DR. PRZEPIORKA: Just one additional comment for Question 2. Another way
that\'s frequently done for other types of procedures is to initiate a
waiting period between the initial discussion and the decision by the
patient, but I have to tell you that that\'s not very practical because
many times patients who are really on clinical trials come from else
where, and sometimes even a 24 hour delay in initiation of treatment is
enough to impose a significant financial burden.

CHAIRPERSON NERENSTONE: Dr. Vanderpool.

DR. VANDERPOOL: Just a brief comment to what Dr. Nelson said about
informed consent. I do think it makes sense to move beyond the document
to questions of process and comprehension of informed consent, and
there\'s been a lot on process, but one thing the FDA or any institution
can do is simply ask the researchers, \"And how od you plan to seek
recruitment for your subjects?\" and determine some of the process that
way.

The other thing is certainly in high risk trials to seek to insure
comprehension of consent by asking, \"Can you repeat what I told you?\"
and you can offer a very simple test to assure comprehension.

But I think those no question the way the committee is going in its
recommendation would mean informed consent does bear a heavy load, which
is the load it does bear in the Belmar (phonetic) report.

CHAIRPERSON NERENSTONE: And the third question: does the Committee
believe that a noninferiority or trials designed to demonstrate an
effect of a new agent on relapse free survival, but unable to assess the
effect on overall survival could constitute acceptable evidence of
efficacy?

Comments? Dr. Fleming.

DR. FLEMING: Let me address the noninferiority question, but just
slightly broaden it first to respond to a question that Dr. Nelson asked
a little bit earlier.

As we look at designs that we could undertake for a vaccine, one of the
approaches is an add-on design, and Dr. Nelson was referring to this
where Interferon would be offered as the control, and the intervention
group would be interferon plus the vaccine, although an option could be
provided to those participants at baseline who after informed consent
had judged that the benefit to risk profile of interferon is not such
that they would want to receive it, and they could then elect to go into
a randomization of observation versus interferon and essentially have
two strata.

Such an approach could be an appropriate design, particularly if one
didn\'t have strong prior evidence that interferon in this case would
be, in effect, modifier. If there isn\'t substantial concern that the
efficacy of adding the vaccine to interferon would be substantially
different than the efficacy of adding the vaccine to observation, one
could, in fact, allow that choice at baseline, essentially forming two
strata for the overall analysis.

Another approach is the one raised in Question 3, which is can we do a
noninferiority comparison. So can we do a head-to-head comparison of
interferon against an intervention such as a vaccine?

My sense about this depends on what the end point is. If the endpoint is
survival, the strength of evidence is not adequate to justify a non-zero
margin. so if we were using survival as the endpoint, I believe we would
have to be looking at superiority.

If we were looking at recurrence free survival, there is sufficient
signal here and precision in the estimate of that signal that one
potentially could justify a margin. If you look at the estimates and the
meta analysis that was done by the FDA, the overall reduction in the
rate of recurrence is, I think, 21 percent with a confidence interval
indicating that it\'s at least 11 percent.

And so if one said, \"All right. I\'ll use that 11 percent estimate and
preserve at least half the benefit, there is still, in fact, a margin
there that could be provided.

Let\'s say that margin, just to go back to the exact data that was
discussed by Dr. Ibrahim, if we said that, for example, the same as a
cure rate of three percent, then essentially if you were assuming that
or you were trying to detect the efficacy of a vaccine that was seven
percent better than \-- seven percent superior, you could rule out that
it was three percent inferior with half the sample size that it would
take to prove superiority.

So there is something here in terms of what the benefits could be in
terms of allowing you to establish efficacy on recurrence free survival
with a more modest sample size.

The difficulty that I have is the last part of this question, and that
is: is such evidence of noninferiority on recurrence free survival
without corresponding evidence about what this means in terms of
survival going to be judged in the end as adequate evidence of efficacy?

And my won view is recurrence free survival is certainly a relevant
endpoint, but not nearly as relevant as being able to establish a
survival impact, and so whereas I think it\'s not possible based on
current strength of evidence to justify a noninferiority design for
survival, it is for recurrence free survival with a very modest margin
here, but I have difficulty in knowing how we would interpret the
results if we simply establish noninferiority on that measure alone.

DR. SIEGEL: Just for clarity for the Committee, that is right at the
heart of what we\'re asking. Our analysis of the current data as
summarized briefly in that paragraph is exactly the same as yours, that
we could, we believe, probably. It depends on the stage a patient is
enrolled and other factors, come with an appropriate margin as ECOG
apparently believes as well.

We\'ve heard for noninferiority on recurrence free survival, but not on
survival, and I think the assessment of this group on the data would
support that conclusion.

That means if we accept a new drug trials, we get applications based on
trials compared to interferon, we will come back to this Committee with
a data set and we\'ll say based on this drug\'s effects on recurrence
free survival, it is similar enough to interferon that we can say with
some level, a high level of certainty that it is effective on recurrence
free survival.

But at the same time we\'ll probably be saying that based on its
similarity to interferon on survival, this trial can\'t tell us anything
about whether it is affecting survival or not affecting survival because
we don\'t have that level of data about interferon.

So we need to know from this Committee is that sort of trial going to
\-- you know, are you going to say, \"Well, why did you even let them do
that trial in the first place since it\'s not going to lead to a drug
approval?\" because if you\'re not going to approve on the basis of a
trial that shows a clear effect on long term, let\'s say, recurrence
free survival form which we can\'t determine even in the long run
overall survival, then it\'s probably not worth doing the trials.

CHAIRPERSON NERENSTONE: Dr. George.

DR. GEORGE: A lot of what I was going to say has just been said in the
interchange between Dr. Fleming and Siegel, but the answer to the
question as I first read it was, yes, but. I mean, yes; yes, you could
do this study, and I strongly agree that you couldn\'t do it with
respect to survival, that is, the noninferiority survival can\'t do \--
it\'s essentially, you know, zero. You don\'t have the same wiggle room
there to define a margin.

But you could with respect to disease free, but would you?

And secondly, what margin would you choose?

I\'m a little concerned about that. I\'m thinking that it would \-- I
haven\'t thought it through completely, but I would think it would have
to be because of the modest evidence, that it would have to be so small
that you would have a pretty big study, and the pretty big study would
end up saying just what you said. If it were successful, it would say
it\'s not inferior with respect to disease free survival; might be with
respect to survival, and that\'s bad.

So I think it is a quandary, and I don\'t know. It might require some
more creative thinking about designs with respect to what you would
require with respect to survival even though you wouldn\'t be able to do
this noninferiority in the usual way.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: Yes. I agree with what the statisticians have said about
the noninferiority, but from a clinician\'s point of view, it\'s going
to be quite apparent to the investigators who\'s getting high dose
interferon and who\'s not, and there will be substantial potential for
bias in determining that progress endpoint, and it won\'t take, given
the magnitude of the benefit, it won\'t take many errors in not
investigating that mole that popped up or not investigating that lymph
node that could or could not be there during that time.

And so there\'s substantial \-- you know, hearing Dr. Temple talk about
sloppiness in noninferiority trials, there\'s substantial potential for
sloppiness in the progression endpoint in such a noninferiority trial.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: Just a brief comment. As to whether or not or a question
whether you would factor in the toxicity profile, I mean, I would think
if I was a patient and you told me interferon for a potential for nine
months, putting cure aside, something else for a potential of 14 months
with a much lower toxicity profile, I might be inclined to take that.

DR. SIEGEL: Well, absolutely, and that\'s why this is perplexing. If you
could show a drug had the same effect on recurrence free survival, say,
a vaccine that\'s extremely well tolerate, the same effect, and you knew
it was a real effect and didn\'t have the toxicity of interferon, you
would think that would be desirable, but again, if that\'s the trial
that\'s done, we would be coming before this Committee not only with a
trial where we don\'t know the outcome on overall survival, but with a
trial that can\'t determine it no matter how many years you follow those
patients because you don\'t have a right group to compare it to. You
have a group that may or may not have an effect on overall survival.

Because that then leaves you with the other options. Adding onto
interferon is certainly one of the options or studying different stages
of disease or, in fact, studying the drug only in those people who opt
to be randomized to placebo and forego interferon therapy.

And so we\'re past that issue, but this is another important study
design issue, and it would be helpful if we can \-- we\'re not coming to
a vote, but I gather, and I think we weren\'t aware how far along ECOG
had progressed in this area, but I wouldn\'t be surprised if these
trials are coming down the way, and it sounds like, you know, the
Committee is going to be potentially faced with them.

And if you\'re thinking that they\'re not the right way to prove a
therapy effective for the purpose of licensure, we need to hear that
now.

CHAIRPERSON NERENSTONE: Dr. Przepiorka.

DR. PRZEPIORKA: I just want to agree with Dr. Nelson regarding the issue
of toxicity, and I think there is a precedent for such a trial right
now. I mean, I said before if I were going to die in five years, I would
prefer to spend four and a half without disease than with disease. So
relapse free survival makes a difference on my quality of life.

So if you go back to your design for quality of life studies, relapse
free survival plus toxicity can, I think, be viewed as a clinical
benefit on which you can improve a drug.

For example, if you had a drug which gives you the same sort of CR rate
in a malignancy and was given as a pill as opposed to interferon, and
you can guess what the drug is, even though you don\'t know the
long-term survival differences, you know, clearly that\'s a drug worth
getting approved.

CHAIRPERSON NERENSTONE: Dr. Kelson.

DR. KELSON: Looking on the other side, if relapse free survival in this
disease was a good stalking horse for survival, and I heard some comment
about that, that the Europeans may feel that way. Then I think it would
be a slam dunk. You wouldn\'t have a problem.

The trouble is looking at the data set that you showed us from the meta
analysis, relapse free survival was not a surrogate for survival.

CHAIRPERSON NERENSTONE: Not seeing any more comments, I\'m going to let
us break for lunch. I\'d like everybody back at two, please, to being
the afternoon session.

Thank you.

(Whereupon, at 1:12 p.m., the Advisory Committee meeting was recessed
for lunch, to reconvene at 2:00 p.m., the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(2:12 p.m.)

CHAIRPERSON NERENSTONE: If the Committee would please take their seat,
we\'ll get started in the afternoon session.

Good afternoon. We\'d like to start this part of the session by again
going around the table and everybody introducing themselves.

Mr. Ohye, if you would like to start.

MR. OHYE: George Ohye, industry rep.

DR. BRAWLEY: Otis Brawley, medical oncologist, Emory University.

MR. McDONOUGH: Ken McDonough, patient representative, North Huntington
VA.

DR. NELSON: Robert Nelson, Children\'s Hospital, Philadelphia, and the
University of Pennsylvania.

DR. PRZEPIORKA: Donna Przepiorka, Baylor College of Medicine, Center for
Cell and Gene Therapy.

DR. FLEMING: Stephen George, Duke University Medical center.

CHAIRPERSON NERENSTONE: Stacy Nerenstone, medical oncology, Hartford
Hospital.

DR. TEMPLETON-SOMERS: Karen Somers, Executive Secretary to the
Committee, FDA.

And, Jody Pelusi, are you on the line? Can you please speak up if you
are?

(No response.)

DR. KELSON: David Kelson, Sloan Kettering, New York.

DR. BLAYNEY: Douglas Blayney, medical oncologist, Pasadena, California.

DR. SLEDGE: George Sledge, medical oncologist, Indiana University.

DR. VANDERPOOL: Harold Vanderpool, Institute for the Medical Humanities,
the University of Texas Medical Branch in Galveston.

DR. TAYLOR: Sarah Taylor, medical oncology and palliative care at the
University of Kansas.

DR. FLEMING: Tom Fleming, University of Washington, Seattle.

DR. ALBAIN: Kathy Albain, medical oncology, Loyola University, Chicago.

DR. CARPENTER: John Carpenter, medical oncology, University of Alabama
at Birmingham.

DR. TIWARI: Jawahar Tiwari, biostatistics, FDA.

DR. CARDINALI: Massimo Cardinali, FDA.

DR. KEEGAN: Patricia Keegan, Center for Biologics, FDA.

DR. SIEGEL: Jay Siegel, FDA.

DR. TEMPLETON-SOMERS: The following announcement addresses the issue of
conflict of interest with respect to this meeting, and is made a part of
the record to preclude even the appearance of such at this meeting.

Based on the submitted agenda and information provided by the
participants, the agency has determined that all reported interests in
firms regulated by the Center for Drug Evaluation and Research present
no potential for a conflict of interest at this meeting with the
following exception.

Dr. Bruce Redman is recused from participating in the Committee\'s
discussions concerning Corixa\'s Melacine

We would like to note for the record that George Ohye is participating
in this meeting as an industry representative acting on behalf of
regulated industry. As such, he has not been screened for any conflicts
of interest.

In the event that the discussions involve any other products or firms
not already on the agenda for which FDA participants have a financial
interest, the participants are aware of the need to exclude themselves
from such involvement, and 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
with any firm whose product they may wish to comment upon.

Thank you.

CHAIRPERSON NERENSTONE: We will turn now to the sponsor presentation,
the appropriate study design and control for the proposed Phase 3 trial
of the investigational new drug Melacine or melanoma vaccine by Corixa.

DR. CHEEVER: It\'s with a great pleasure that this afternoon I have the
opportunity to present the clinical development of Melacine vaccine;
that the purpose of today\'s study is to discuss the proposed second
pivotal trial of Melacine vaccine as adjuvant therapy for intermediate
thickness Stage II melanoma in patients that are HLA-A2 and/or HLA-C3.

The first point I want to make is that the category of patients that
were studied is not the category of melanoma patients that were
discussed this morning. This morning we discussed patients primarily
that were Stage III that had no positive disease. These patients have no
negative disease.

This morning we talked primarily about those patients with Stage 2 that
had thick tumors, meaning tumors greater than four millimeter, the
primary tumor. In this circumstance we\'re dealing with intermediate
thickness Stage II. Those are patients with primary tumors of less than
four millimeter.

In large part this morning\'s discussion was silent on this group.
Despite that, this group comprises approximately 25 percent of melanoma
patients. The five year survival is between 63 and 79 percent. Even
though they\'re less than four millimeters, their survival depends upon
a thickness within that parameter.

There is no approved adjuvant therapy to prevent relapse in this disease
category, and there\'s no adjuvant therapy routinely being recommended,
and the one comment that Dr. Kirkwood made this morning in reference to
this group, if I quote him correctly or paraphrase him, that there is no
therapy that has been tested or is approved for this category of
patient.

This clearly is an unmet medical need. The Southwest Oncology Group, in
an attempt to meet this unmet need, conducted a trial called SWOG 9035,
and this slide will very quickly go over the conclusions from that SWOG
9035 trial, but please be aware that I\'ll only present the capsule
summary at this point in time and will go over each one of these points
in detail later on in the presentation.

SWOG 9035 compared Melacine versus observation in patients with
intermediate thickness Stage II melanoma. SWOG\'s analysis demonstrated
a nonsignificant trend in relapse free survival for Melacine in the
intent to treat population.

There was a highly significant relapse free survival benefit for
Melacine in patients that expressed two of five predefined HLA antigens.
The domino effect was in patients who expressed HLA-A2 or HLA-C3 or a
combination of both of them. And for the rest of the presentation I\'m
terming patients who have A2 or C3 or both as A2/C3 positive.

In this A2/C3 positive population, Melacine was associated with a highly
significant increase in both relapse free survival and overall survival.

Accelerated approval for A2/C3 positive patients was discussed with the
FDA and was considered not to be an option because these patients were
subpopulation of the intent to treat population.

A second pivotal trial that confirms the efficacy of Melacine in A2/C3
patients will be required for approval. Therefore, the goal of Corixa is
to replicate SWOG 9035 as closely as possible, but with only A2/C3
positive patients in order to confirm the benefit of the vaccine in this
particular patient population.

However, there area number of issues that affect the design of the
second pivotal trial. Importantly, the first pivotal trial took ten
years, and the second pivotal trial may take up to another decade.

Given this time frame, the key issues of trial design need to be
addressed now in order to design this second pivotal trial sufficiently
to confirm the first pivotal trial for regulatory approval.

Since initiation of this trial a decade ago, there have been some
substantial changes in the standard practice of melanoma that affect
attempts to replicate the first trial. At the suggestion of the FDA,
guidance from ODAC is being sought today on trial design.

The primary question is whether the patient populations chosen are
appropriate for an observation only control arm.

The presentation today will have as topics an overview of Stage II
melanoma, an overview of the clinical development of Melacine vaccine,
detailed results of SWOG 9035, issues affecting further development of
the vaccine, the proposed second randomized pivotal trial, and finally,
the issues for ODAC and the FDA.

The first topic will be an overview of Stage II melanoma, and I should
read into this an overview of intermediate thickness Stage II melanoma.
I can gloss past this slide. Melanoma is a substantial disease. I think
everyone is aware of that.

The outcome of the disease is really dependent upon the stage at the
time of diagnosis. Stage I and II are differentiated primarily by size
of the primary tumor. Stage III are those patients that have regional
lymph nodes involved, and Stage IV are those that have disseminated
disease.

This morning the discussions on interferon focused primarily on patients
with Stage III and that portion of Stage II that had tumors of greater
than four millimeters. For the talk today or this afternoon, we will be
focused on Stage II patients, but those that have the smaller tumors,
the intermediate thickness tumors.

The intermediate thickness Stage II melanoma is defined as tumors that
are between one and four millimeter by the old AJCC staging system that
was discussed this morning and was in place when the SWOG trial was
initiated. That thickness was 1.5 to four millimeter.

Now, the new AJC staging system quantifies the tumor thickness as one to
four millimeter. All patients are node negative. All patients are
metastasis negative, and, again, the five year survival is between 63
and 79 percent depending upon the thickness as well as the new
prognostic criteria, which is ulceration.

Twenty-four percent of the patients were in this category in the AJCC
database, which was included as Balch\'s manuscript in your briefing
document.

This slide, also taken from Balch\'s article in your briefing document,
shows that 15 years disease specific survival for Stage II melanoma, and
this is the new AJCC staging systems. For this morning when we spoke of
Stage IIB, we were not dealing with the same Stage IIB. Rather, we were
dealing primarily with Stage IIC in the new system, which is not on the
slide. A Stage IIC would have had a worse 15 year overall survival than
what is up here.

What I really wanted to point out with this slide is that patients with
Stage IIA have approximately 80 percent five year survival. It\'s
patients with IIA that were in the SWOG trial and will be on the
proposed trial.

Also, some patients with Stage IIB, in particular those patients that
had tumors less than four millimeter, and those patients had a slightly
less optimistic outcome.

The other point to make from this slide really is that even though the
five year survival is 80 percent, these patients continue to relapse and
die over 15 years here, and even though a plateau was spoken of this
morning, that the AJCC database really does not discern a plateau to 15
years. The reason we saw a plateau this morning could have been because
if there were a lack of patients far out.

But these patients with Stage II melanoma continue to relapse up to 15
years, and patients that relapse, in general, in general, die.

Despite this substantial nature of the disease, there is no adjuvant
therapy to prevent relapse. There are no approved drugs. There are none
routinely recommended. There\'s only one ongoing U.S. pivotal trial in
this category of patients, and that\'s ECOG 1697, which was mentioned
briefly this morning, and it should be noted that this is a trial of
observation versus four weeks of INTRON-A; that the cooperative groups
have not take upon themselves yet to test the approved proven effective
regimen of interferon in this category of disease.

There are no other ongoing U.S. Phase 3 trials in this disease. So given
these points, it\'s highly likely that we\'re going to be back here a
decade from now still giving you the same message that there are no
approved drugs and no routinely recommended drugs for this category of
disease.

The next topic is the overview if the clinical development of Melacine
vaccine. These are primarily time lines, but first start with the
vaccine itself. The vaccine has two components, a melanoma lysate and an
adjuvant, detox. adjuvant; that the lysate is the lysate from two
melanoma lines. One is a rapidly growing, very aggressive melanoma. One
is a slow growing, less aggressive melanoma.

They were originally chosen to represent a spectrum of the disease of
melanoma. We know now ‑- we didn\'t know at the outset, but we know now
that it contains virtually all of the antigens that we now consider to
be melanoma vaccine candidates, including gp100, the gangliosides,
Melan-A, the mage (phonetic) antigens, tyrosinase, tyrosinase related
proteins, as well as high molecular weight melanoma associated antigen
or chondroitin sulfate.

If you just inject antigens into patients, even the foreign, you do not
get much of immune response. In order to get a substantial immune
response, you really have to inject the antigens with an adjuvant. In
this circumstance we\'re using a detox. adjuvant, which is a combination
of cell wall skeleton derived from mycobacterium phlei, as well as MPL,
or monophosphoralipid A, derived from Salmonella Minnesota, and we have
substantial experience with this particular adjuvant.

The clinical development of Melacine in advanced stage patients began 17
years ago now in 1985 with trials initiated by Malcolm Mitchell, then at
USC. In 1988, the trials were taken over by RIBI Immunochem, which was
later bought by Corixa. RIBI Immunochem treated over 300 patients with
Stage IV disease.

An independent review of 198 of these patients validated six percent or
11 objective responses. Of these objective responses, most importantly
there were five complete responses and four of those complete responses
were maintained at seven plus the ten plus years at the time of the
independent review.

Moreover, the vaccine was well tolerated, had a reasonable safety
profile.

Based on the data in advanced patients, Melacine was approved for use in
Canada in the year 2000 for disseminated malignant melanoma.

In 19990, the decision was made to test Melacine in Stage II patients as
adjuvant therapy. This was based on the modest efficacy, as well as low
toxicity in advanced patients, and the commonly accepted theory that
anything that works in advanced disesae is likely to work must better as
adjuvant therapy because of the smaller tumor burden, because of less
tumor induced immunosuppression, and because of the longer time over
which the immune response has to operate.

In 1990 then, the Southwest Oncology Group initiated design planning for
the trial 1935. In April of 1992, SWOG enrollment began.

At about the same time, Dr. Mitchell published in JCO analysis of his
advanced stage patients showing an association of HLA phenotype with
response to Melacine.

Okay. His results, again, were in advanced patients. He analyzed the
outcome of 70 patients with disseminated melanoma, and what he
demonstrated was that there were five HLA types associated with Melacine
benefit, and I\'ll read these the first time, but they\'re the same on
multiple subsequent slides. They were HLA-A2, A28, B44, B45 and C3.

His association really made tow points, and the first point was that
there was benefit from Melacine in patients that expressed two or more
of these five HLA, and second, the benefit from Melacine was strongest
in patients who expressed HLA-A2 and/or HLA-C3, again, A2/C3 positive
patients.

Based on Mitchell\'s publication and analysis of the data in advanced
patients, SWOG in 1994 began to HLA type all of their patients.

In 1996, their enrollment was completed. At that time they enrolled 689
patients. They had been able to HLA type 80 percent of their patients.
Out of those, approximately 70 percent that were typed were typed
prospectively and 30 percent were typed retrospectively.

In 2000, SWOG performed their primary data analysis, and at that time,
there was a relapse free survival benefit for the vaccine in all
patients\' intent to treat analysis with a P value of .04.

In September 2000, SWOG analyzed HLA data and demonstrated a relapse
free survival benefit for vaccine in patients that expressed two or more
five of the predefined HLA. Again, this was Mitchell\'s first finding,
which was confirmed by SWOG.

Mitchell\'s second finding was that there was benefit in A2/C3 positive
patients. This was also confirmed by the SWOG analysis. There was a
relapse free survival benefit from the vaccine in A2/C3 patients with a
P value of .004.

This part of the talk is to just present you with an overview of the
time line, and I\'ll get back and present the data later on in the talk.

In September of 2000, we had an end of Phase 3 meeting with the FDA and
discussed at that time an additional data sweep. The additional data
sweep was to try to confirm the outcome of the study at a time, after a
greater time had occurred and after more events had occurred.

Between November 2000 and April 2001, SWOG conducted the data sweep. In
May 2002, Corixa analyzed the follow-up data. The relapse free survival
in all patients\' intent to treat analysis which previously had been
statistically significant lost its statistical significance with a P
value of .141.

However, the relapse free survival in A2/C3 positive patients continued
to be positive, with a P value of .005. Moreover, in a new analysis of
overall survival, SWOG demonstrated a benefit for the vaccine in A2/C3
positive patients with a P value of .003.

These analyses that were performed by Corixa were later confirmed by
SWOG.

In June of 2001, the results were submitted to the FDA. In October 2001,
accelerated approval as adjuvant therapy in Stage 2 A2/C3 positive
patients was discussed with the FDA, and it was decided by the FDA that
a second Phase 3 trial would be required.

Therefore, today we\'re consulting you all for advice concerning
appropriate patient population in order to confirm the first pivotal
trial results in this disease population.

The third topic is details of the result of SWOG 9035. SWOG 9035 was
titled randomized trial of adjuvant immunotherapy with an allogeneic
melanoma vaccine for patients with intermediate thickness, node negative
malignant melanoma categorized as T3N0M0. This is a multi-centered, open
labeled trial conducted by SWOG with IND held by Corixa.

The study coordinators are Vern Sondak and Jeff Sosman, Ray Kempf, Ralph
Tuthill and P.Y. Liu.

The objectives of the trial were to compare Melacine versus observation
for relapse free survival and overall survival.

Number two, to evaluate the toxicity of Melacine as adjuvant therapy.

And, number three, to explore the interaction between patient HLA types
and vaccine effectiveness for relapse free survival and overall
survival.

This third objective was added by protocol amendment in response to
Mitchell\'s analysis. It was added in September of 1994.

For trial design, after the primary tumor was removed, patients were
stratified and randomized in a one-to-one ratio between observation and
vaccine. The vaccine was given intramuscularly, 40 doses over the first
two years.

The observation group and the vaccine group were followed equivalently
for disease relapse. They were evaluated every three months for the
first two years and then every four months for the next three years and
then annually thereafter.

The major inclusion criteria were primary cutaneous melanoma that had to
have been completely resected. Patients could have been clinically or
pathologically nodally staged. They were categorized either clinically
or pathologically as T3N0M0.

If clinically staged, that meant that the regional nodes were not
palpable. A number of the patients, 25 percent had the regional node
dissection, but a regional node dissection and sentinel node evaluation
or biopsy was not a requirement for the trial. There could be no
evidence of metastatic disease.

The patients were categorized as T3 and 0M0, and the circumstance T3 was
defined by AJCC staging criteria as being 1.5 to four millimeters in
thickness or in circumstances where for technical reasons thickness
could not be determined, T3 mean Clark\'s Level IV invasion.

The technical reasons for which thickness couldn\'t be determined were
things such as shave biopsies, and again, this corresponded to Stage IIA
in AJCC staging system, and just to reiterate once more, this morning we
were discussing primarily Stage IIB disease as well as Stage III
disease.

Patients were stratified according to gender. In general, females do
better than males with this disease. They\'re stratified for lymph node
dissection. Obviously patients that have a lymph node dissection do
better than those in which it\'s unknown whether the lymph nodes are
positive or negative. All patients with positive lymph nodes were
excluded from the trial.

They\'re stratified according to primary tumor thickness. In general
patients with smaller tumors or less thick tumors do better than
patients with thicker tumors. Pardon me. Thin tumors do better than
thick tumors.

In total, 689 patients were randomized with 346 patients in the vaccine
arm and 343 patients in the observation arm.

All treatment assignments were based on entry pathology. Centralized
pathology and surgical reviews were conducted after randomization.

The data cutoff for the relapse free survival analysis was February of
2000. The cutoff was predefined. It was determined when a predefined
number of event had occurred as per the SWOG Statistical Center. At that
point 33 percent of the patients had either relapsed or had died.

The median follow-up for all patients was 4.1 years. The minimum time
since registration of the last patient at that point was three years.

The vaccine and the observation arms were comparably distributed between
the stratification factors of tumor thickness, lymph node staging and
gender. Ulceration is now known to be a prognostic factor. It turns out
that the vaccine and observation arms were equally distributed between
patients that had ulcerated tumor versus no ulcerated tumor.

There was a trend towards more tumors in the vaccine group on the
extremity, but that did not reach statistical significance.

SWOG\'s analysis of the 2000 database demonstrated that all three
stratification factors had a significant effect on relapse free
survival, as expected and predicted, with thin tumors doing better than
thick tumors, females doing better than males, and patients with lymph
node staging doing better than patients who did not have lymph node
staging.

Relapse free survival was the primary endpoint. SWOG\'s analysis of the
2000 database demonstrated that the vaccine had a significant effect on
relapse free survival. It was significantly longer for vaccine versus
observation, the Cox model, intent to treat population with a P value of
.040; the hazard ratio of .76.

These relapse free survival curves point out the benefit for vaccine
versus observation in all patients, again, with a P value of .40
adjusted for stratification factors. Again, this slide demonstrates
vaccine significantly prolonged relapse free survival in all patients in
the 2000 database.

However, upon the data sweep, there were an additional 27 events, and
the relapse free survival benefit for the vaccine lost its statistical
significance. The curves came together at approximately six to six and a
half years, demonstrating again following a data sweep that the
significant benefit for the vaccine was lost.

The next topic that I want to talk about is the association between HLA
and Melacine benefit, but I first want to set the stage again for why
SWOG looked at HLA and why they did the particular analyses that they
did.

Mitchell\'s study, his analysis in 1992 demonstrated that five HLA were
shown to be associated with Melacine benefit and disseminated melanoma.
Mitchell demonstrated two things: first, a benefit for Melacine in
patients with two or more of these five HLA antigens; and, second, a
benefit for Melacine was really strongest in patients that expressed
either HLA or HLA-C3 or both.

Because of Mitchell\'s analysis and findings in advanced stage patients,
the SWOG amended their trial in early stage patients in 1994 to examine
whether similar benefits occurred in these early stage patients.

SWOG\'s distribution of HLA antigens was similar to the Caucasian
population in general. This is the population that\'s at risk for this
disease with 46 percent of the patients being HLA-A2, 29 percent of the
patients being HLA-C3, and you can read the rest as well as I can.

The point of this slide really is that the combination of A2 plus C3
occurred in 58 percent of the patients. The 46 percent and the 29
percent don\'t add up to 48 percent, clearly. A number of patients
expressed both A2 and C3.

But the point is this is a substantial subset of the entire population.

Mitchell\'s analysis demonstrated that patients that expressed two or
more of these HLA antigens benefitted from the vaccine. The SWOG
analysis demonstrated the same. In patients with two or more matches
there was a benefit for vaccine over observation with a P value of .002.

By contrast, in the subgroup of patients with zero to one match, there
was no benefit for vaccine versus observation.

Okay. Mitchell demonstrated that HLA-A2 and HLA-C3 were the two HLA
antigens with strongest association with benefit from the vaccine. SWOG
analyzed each one of the five predefined HLA antigens and demonstrated a
benefit for HLA-A2 with a P value of .009; a benefit for HLA-C3 with a P
value of .02; HLA-B44 was not statistically associated with benefit, and
there were not enough HLA-A28 or B45 patients in order to appropriately
analyze vaccine benefit.

SWOG went on then to analyze the potential correlation of the benefit
with the A2/C3 population and demonstrated that the vaccine had
significant benefit on relapse free survival with a P value of .002 and
a hazard ratio of .56.

These relapse free survivals are depicted on this slide of the February
2000 database vaccine versus observation in A2/C3 positive patients. The
vaccine significantly prolonged relapse free survival with a P value of
.002.

The next slide shows the same two groups, vaccine versus observation in
the A2/C3 positive patients, but in the May 2001 database following the
data sweep showing that the statistical significant benefit for the
vaccine in the subset was not lost on the data sweep with a P value at
.005.

The question was also asked whether or not the vaccine had a benefit in
patients that were A2/C3 negative, and the answer, it did not. This is
vaccine versus observation. In the A2/C3 negative patients, a P value of
.77.

The question was also asked as to whether expression of A2/C3 was in and
of itself a prognostic factor, and it was not. In patients that were
A2/C3 positive and only observed, the outcome was the same as patients
that were A2/C3 negative and were only observed.

Therefore, A2/C3 expression without vaccine did not prolong relapse free
survival.

The five year relapse free survival estimate for patients that were
A2/C3 positive and received the vaccine was 75 percent versus 63 percent
for the same category of patients that were observed only. Patients that
were A2/C3 negative, five year relapse free survival was 62 percent
irrespective of whether they were observed or whether they received the
vaccine.

Following the data sweep with the May 2001 database, overall survival
was also examined, and it was determined that relapse free survival was
also reflected in overall survival in a subset of patients that were
A2/C3 positive, with a P value of .003.

The same additional two questions were asked. The first question is
whether or not there was an increase in overall survival in patients who
were A2/C3 negative, and there was not.

And the last question was whether or not the expression of A2/C3 was in
and of itself a prognostic factor for overall survival, and it was not
on the survival curves.

The summary of the follow-up analysis by Corixa of the May 2001 database
then. The vaccine is effective in prolonging relapse free survival.
A2/C3 positive patients, a P value of .005. The vaccine is effective in
prolonging overall survival in A2/C3 positive patients with a P value of
.003.

These analyses by Corixa were subsequently confirmed by SWOG and have
been submitted for presentation at ASCO this year.

The trial also looked at vaccine safety in patients with early stage
disease. Adverse events were evaluated in the treated population. They
were assessed by SWOG toxicity criteria. They were recorded only for the
Melacine patients. They were not recorded for symptoms that were
certainly most likely due to disease or other nontreatment causes.

Ninety-six percent of the patients experienced at least one adverse
event. The majority of the adverse events were mild to moderate.
Twenty-three percent of the patients had a maximum of Grade 1 toxicity.
Sixty-five percent of the patients had a maximum of a Grade 2 toxicity.
Nine percent of the patients had a maximum of Grade 3 toxicity, and none
of the patients had a Grade 4 toxicity or death. The adverse events were
comparable in the A2/C3 positive and in the A2/C3 negative populations.

This slide lists the Grade 3 toxicities that were reported in three or
more patients. This includes injection site reactions, malaise and
fatigue, diarrhea, transient vision abnormalities and fever in the
absence of infection.

The transient vision abnormalities were seen in three patients, less
than one percent. In each case the vision abnormalities were associated
with other symptoms, such as headache or nausea. In each circumstance
the treating physician felt that the symptoms were minimal enough that
all of the patients had additional doses of the vaccine; that transient
visual abnormalities did not recur in any of the patients, and in none
of the patients was there any evidence of retinitis.

The summary then of SWOG 9035 is that Melacine significantly improved
relapse free survival and overall survival in patients who expressed
HLA-A2 and/or HLA-C3. The toxicity was minimal. These results are highly
encouraging for patients with melanoma and for cancer vaccines in
general; that the results are consistent with the prediction that in the
post genomic era that we\'re in currently, therapies will be tailored to
patients\' genetic capabilities to respond.

And this correlation between HLA type and outcome makes biologic sense.
HLA or human leukocyte antigens lay a central role in immune
surveillance, immune response and immune regulation; that the role for
HLA is to bind peptide fragments of antigens. HLA presents peptide
fragments of antigens to T cells and activates T cells, triggers T cell
responses.

The HLA antigens are highly polymorphic. Each particular allele, each
particular HLA antigen binds a paritcular subset of peptides, and each
HLA binds a different subset of antigenic peptides. It\'s the peptide
binding of HLA antigens that governs responsiveness versus
nonresponsiveness to vaccines.

The number of circumstances in infection disease vaccines where
responsiveness versus nonresponsiveness is dictated by HLA or low
responsiveness versus high responsiveness is dictated by HLA. The
vaccines include Hepatitis B, influenza, as well as HIV.

So it makes some sense that we would see the same correlation in cancer
vaccines.

Despite the correlation of vaccine benefit with particular HLA antigens,
the mechanism of the benefit from the vaccine is unknown. There are
several possible explanations, including HLA-A2 and C3 or Class I HLA.
They are known to present antigens that activate cytotoxic T cells. So
A2 and C3 may preferentially present one or more of the Melacine
melanoma antigens within Melacine to cytotoxic T cells.

Alternatively A2 and C3 may be linked to other polymorphic immune
response genes that themselves are responsible for benefit of the
vaccine, and the next slide basically lists the genes that are on
chromosome 6 that are in proximity to Class I genes that are polymorphic
and have functions that relate to immune response, including the MICA,
MICB genes, which activate gamma delta T cells, TNF heat shock protein
which chaperons antigens, the complement components; Class II HLA, which
is necessary for activating cytotoxic T cells, as well as generating
antibody responses; the TAP genes that are involved in antigen
degradation and presentation on T cells.

Nunley (phonetic) chromosomes are also other uncharacterized genes with
as yet unknown function.

It also needs to be noted that there\'s a high level of linkage
disequilibrium between HLA and these particular immune response genes,
meaning that quite often they segregate along with HLA genes and define
distinct immune response haplotypes.

Parenthetically even though we don\'t know what the mechanism of
Melacine is, I would also contend that we aren\'t any closer to
understanding the mechanism of interferon either.

The next topic are issues affecting further development of the vaccine.
Since initiation of SWOG in 1935, there have been a number of changes in
standard care that in effect attempts to replicate and confirm the
results of SWOG 9035.

Number one, INTRON has been approved as adjuvant therapy in patients
with high risk for recurrence. Again, these patients are considered to
be intermediate risk for recurrence.

The next AJCC staging system is in use with different cutoffs and
parameters, and the lymphatic mapping of sentinel node biopsies is
commonly employed.

I don\'t think we need to dwell on this slide. We talked about this
extensively this morning, but I only want to make the point that the
general assumption going into this morning\'s meeting and what I took
out of the meeting is that INTRON-A is approved for lesions of greater
than four millimeter without or with lymph node involvement, and the
corollary is that INTRON is not approved for lesions of less than four
millimeter without lymph node involvement.

Okay. The new AJCC staging system, which you have a copy of in Balch\'s
manuscripts in the briefing document, has thickness break points at one,
two, and four millimeters as opposed to the old system, which is .76,
1.5, and four millimeters.

SWOG 9035 entered patients with lesions of 1.5 to four millimeters
according to the prior AJCC staging system.

The new staging system also up stages patients with ulcerated primary
lesions.

The standard practice now is to subject patients to lymphatic mapping
and sentinel mode biopsy. The primary tumor is greater than one
millimeter. This divides patients who are previously clinically staged
as lymph node negative into pathologically staged lymph node positive
patients and lymph node negative patients. Patients with pathologically
staged positive lymph nodes are now commonly offered INTRON-A.

In SWOG 9035, 25 percent of the patients were pathologically staged, 75
percent only clinically staged. In the proposed trial, according to
standard practice now, all patients will be pathologically staged
whenever technically feasible.

As a consequence then, the proposed patient population will exclude
patients with lymph nodes containing microscopic or occult tumor that
was detectable only by biopsy. This may then lower the risk of the study
population for recurrence.

Okay. The next topic is the proposed second randomized pivotal trial.
The proposed trial will try to mimic or reproduce as closely as possible
SWOG 9035. It will include Stages IIA and IIB. Again, this is not the
IIB that was discussed this morning. Rather IIB by the new staging
system, which we\'ll show in a moment.

These patients are deemed to be at intermediate risk for relapse. The
higher stages will be excluded as being not represented in SWOG 1935,
and they may be interferon candidates.

Lower stages will be excluded because they were not well represented in
SWOG 1935, and the risk of recurrence in these patients will be to low.

Okay. The major eligibility criteria will be histologically diagnosed
surgically removed Stage IIA or IIB cutaneous melanoma. All patients
will be HLA typed and will be HLA-A2 and/or HLA-C3. All patients will
have lymphatic mapping and sentinel node biopsy if technically feasible.
There will be no evidence of metastatic disease, and there can be no
prior or planned INTRON-A chemotherapy, radiation therapy, or other
biological response modifiers planned.

In SWOG 9035, patients were entered according to the old AJCC staging
system. The patients on the trial were those with Stage IIA T3 tumors.
These tumors are 1.5 to four millimeter.

In the new proposed AJCC staging system \-- I say \"proposed,\" but
it\'s commonly being used today \-- in this new AJCC staging system, the
proposed patient population are those with Stage IIA. Those are tumors
of 1.5 to two millimeter with ulceration. The five year survival in
those is 77 percent or Stage T3A. These are tumors of two to four
millimeter without ulceration. The five year survival is 79 percent.

And finally, half of the patients or the better half of patients with
Stage IIB will be included. Those are patients with tumors of two to
four millimeter, with ulceration. The outcome in these, five year
survival is 63 percent.

Excluded will be the half of IIB that have tumors of greater than four
millimeter because these tumors were not included in the initial trial.

Patients will be stratified according to pathologic stage. They\'ll be
stratified according to gender, and they\'ll be stratified according to
the primary site of tumor extremity versus head and neck and trunk.

A total of 700 patients that are A2/C3 positive will be entered on the
trial. They\'ll be randomized in a one-to-one ratio between vaccine and
observation. Approximately 350 patients per arm.

The estimated five year relapse free survival based on SWOG 9035, as
well as the AJCC database will be 70 percent in the observation arm
versus 80 percent in the vaccine arm. Enrollment will take approximately
three to four years.

The data cutoff date for the primary analysis will be five years after
enrollment. This will allow an 80 percent power to detect this ten
percent difference.

The trial design will be essentially the same as SWOG 9035. Patients
will have primary tumor removed. They\'ll be stratified and randomized
between observation and vaccine. The vaccine will be given over two
years, 40 doses. Patients in both groups will be evaluated equivalently
for disease relapse.

Data points will be efficacy and safety. The efficacy will be in the
intent to treat population. The primary endpoint will be relapse free
survival. The secondary endpoint will be overall survival.

Patients will also be evaluated for safety by evaluating for adverse
events. We will look for adverse events both in the Melacine and the
observation arms.

Finally, the issues for ODAC and FDA. Our first question: is it agreed
that treatment with INTRON-A is not necessary for the proposed
intermediate risk patient population that includes patients with Stage
IIA and IIB tumors?

Our second question is: can or should patients with Stage IIIA tumors
\-- that\'s N1a \-- especially if less than four millimeters, but with
one positive microscopic lymph node detected by sentinel node biopsy, be
included in the proposed trial?

And this issue can be, I think, best pointed out by going back to this
table which was taken out of Balch\'s manuscript in the briefing
document.

The proposed trial as planned now will include patients in Stage IIA and
IIB. The five year survival in those categories is between 63 and 79
percent.

This category of Stage IIIA, patients that have occult or microscopic
metastases diagnosed because of virtue of the fact that they have
sentinel node biopsy, have a five year survival of 69 percent, which is
equivalent, and even though we don\'t have this data, if we look at only
those tumors that are less than four millimeter, the five year survival
is probably greater than the 69 percent.

So, in summary, adjuvant therapy for intermediate thickness Stage II
melanoma is an unmet medical need. In SWOG 9035, Melacine prolonged
relapse free survival and overall survival in Stage II patients who
expressed two or more of five predefined HLA types or expressed HLA-A2
and/or C3.

The mechanism by which Melacine provides a benefit is unknown, but is
associated with immune response genes.

Finally Corixa needs consensus on the second Phase III trial design to
replicate SWOG 9035 in order to confirm the benefit of Melacine in this
patient population and for regulatory approval.

Thank you very much for your attention. We welcome questions from ODAC
members and from the FDA, and to help field the questions we have SWOG
representatives with us. We have John Thompson. Maybe you could just
come up to answer questions up here.

We have John Thompson who is a Professor of Medicine at the University
of Washington; Jeff Sosman, a Professor of Medicine at Vanderbilt
University; and Walter Urba, Director of Cancer Research at the Earl
Childs Research Institute in Portland, Oregon.

And to help field questions from Corixa, we have Cindy Jacobs, who is
Senior Vice President of Clinical Development; Monica Krieger, Vice
President of Regulatory Affairs; Chuck Richardson, Senior Vice President
and Manufacturing Site Manager; Ken Von Eschen, Medical Director; and
Heather Tully, the Manager of Biostatistics.

So I turn the forum back to ODAC.

CHAIRPERSON NERENSTONE: Thank you very much.

Are there any questions from the Committee to the sponsor?

I have a first question about the trial design. Being that it is going
to be a relapse free survival and not overall survival endpoint, has
there been any thought to a placebo controlled design?

DR. CHEEVER: There are a couple of issues with that. I have the
lavaliere on.

Okay. First, it\'s certainly something that we have considered. There
are a number of issues. First of all, it\'s difficult to come up with a
true placebo where the patient and their physicians don\'t know what it
is. It will look different and will have a different local reaction.

The second is that we think that the findings in SWOG 9035 are very
compelling and would like more than anything to absolutely repeat this
trial as closely as possible so that we can either confirm that the data
is correct or refute it.

I think that it\'s very important for melanoma patients and it\'s, I
think, very important for the field of cancer vaccines to precisely
repeat the trial as it was. Maybe you have a different answer.

CHAIRPERSON NERENSTONE: I guess I understand your concern that it\'s not
going to look alike. I think your data would be that much stronger.

The problem of investigator bias in the endpoint when recurrence
happens, I think, is going to be very important, and if the investigator
knows that the patient is on observation only, the likelihood of
investigating a cough that gets worse is probably a little bit more in
terms of looking to see if it\'s related.

DR. CHEEVER: John, maybe you can answer this.

DR. THOMPSON: Well, I was very involved with this study, as were my
colleagues here from SWOG, and I think it\'s safe to say that as
clinicians taking care of melanoma patients, that when we evaluated
patients in follow up on the protocol which was done on a regular basis
every three months during the first two years and then every four months
in years three through five, that if patients presented with symptoms
that were suspicious of recurrence, those symptoms would have been
investigated regardless of which arm the patient was on.

DR. SOSMAN: Yeah, in terms of the adjuvant, which is a question, I
think, that was referred to, I think Dr. Cheever made a very good point
that we\'ve discussed ourselves in that there\'s been a lot of mistakes
made in vaccine trials in the past, and the real hope is that we really
look at the whole product versus no treatment, and if there was an
adequate placebo, that may be an idea, but it would be very hard, and to
look at the whole vaccine versus part of the vaccine I think just is
fraught with problems.

And we\'ve been down that road other times in vaccine trials.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: I share the Chair\'s concern about the bias on the part of
investigators who might know which treatment a patient is receiving, and
you\'ve heard the concern.

Second, what would happen if a patient had a sentinel lymph node
dissection in IA, microscopic disesae, and that was discovered? Would
they go on to have a completion lymph node dissection of that lymph node
bed or do you project calling it a day and going on?

DR. THOMPSON: That was not actually described in the protocol, but I
think most of the institutions participating in this study had that as
their paradigm, that if a sentinel node was positive, that those
patients did have a completely lymph adenectomy.

DR. SOSMAN: Obviously that is a question, and even ACOSOG (phonetic)
discussed looking at that question, but I don\'t think that\'s something
we have to be concerned about. They\'re not going to do that study
because it is so ingrained at least in 2002 that almost all patients who
have sentinel nodes that are positive go on to completion node
dissection.

So I don\'t think that\'s something to be concerned about.

DR. BLAYNEY: Even the microscopic?

DR. SOSMAN: Well, that\'s what \--

DR. BLAYNEY: The immunohistochemistry staining that\'s done afterwards?

DR. SOSMAN: Well, I think our definition we haven\'t talked about in
detail, but likely we\'re going to try to be as consistent as possible
with defining what is positive sentinel node, and that gets into detail
that we\'ll have to work out as we put the trial together.

CHAIRPERSON NERENSTONE: Dr. Przepiorka.

DR. PRZEPIORKA: Not to belabor the issue, but just to go on with it,
detox., has anyone looked at detox. alone as a vaccine in melanoma or
any other malignancies? Does he have any activity?

DR. CHEEVER: No, we have not looked at detox. alone for activity alone.

CHAIRPERSON NERENSTONE: Dr. Kelson.

DR. KELSON: You\'re proposing to do the primary endpoint analysis five
years after the last patient is entered into the study. So the data will
be very mature, and the curves for both relapse free and overall
survival clearly separated by five years.

Why is the primary endpoint RFS instead of overall survival if you\'re
not going to do the analysis until that point anyway?

DR. CHEEVER: Heather, can you answer that?

MS. TULLY: We have \--

CHAIRPERSON NERENSTONE: Excuse me. Please use a microphone and identify
yourself.

MS. TULLY: My name is Heather Tully. I work at Corixa. I\'m a
biostatistics manager.

Let me give you a little background into the way that we sized the
trial. I think that might be helpful.

In the 323 patients in the SWOG study who were A2/C3 positive, we had
about a 73 percent relapse free survival in the vaccine arm and about 64
percent five year relapse free survival in the observation arm.

We were concerned because that trial started in 1992, and there have
been numerous changes in the standard practice that we should increase
our estimates of five year relapse free survival to size the trial, and
so we based the size of the trial on 80 percent for the vaccine arm and
70 percent for the observation arm.

And at that point after five years, we would have about 80 percent power
for relapse free survival.

DR. KELSON: What would the similar numbers be for survival?

DR. TULLY: I don\'t exactly know, except it wouldn\'t be that high.

DR. FLEMING: I did those calculations. Can I comment?

CHAIRPERSON NERENSTONE: Sure.

DR. FLEMING: I took the data as had been presented to us on pages 13 and
14 in the briefing document. There are also corresponding slides that
would have been presented, and on page 14 in the briefing document, for
example, the hazard ratios are given there for both relapse free
survival and for overall survival in the A2/C3 subgroup.

And the reduction in relative risk is 44 percent for relapse free
survival. It\'s 57 percent for survival. Essentially the 80 versus 70
corresponds to a 38 percent reduction.

If one takes a more cautious approach and says the overall observed
reduction on page 14 in the A2/C3 subgroup for survival is 57 percent,
you say suppose it\'s only 40 percent. If it\'s only 40 percent, given
the actual survival curves and the amount of information that we have,
by my calculation 687 patients would give us a targeted 120 events,
which is exactly what you need to get 80 percent power to pick up a 40
percent reduction.

And in fact, if you have 80 percent power to pick up a 40 percent
reduction, your observed reduction has to be 30 percent for statistical
significance, remembering if you have 80 percent power for a given
reduction, the observed has to be two thirds to three quarters of that
to achieve significance.

So if the sponsor looks at these results and sees a 57 percent reduction
in risk and thinks that a subsequent trial with 700 patients could
reasonably be expected to achieve half that amount of reduction in risk,
observe 30 percent, that would achieve statistical significance.

So I\'ve wondered the same thing. Given that there are the uncertainties
about the objectivity with recurrence free survival and all of the
discussions from this morning about whether recurrence free survival
truly reliably predicts survival, this study with 700 patients is
adequately powered to achieve significance on survival if the observed
reduction is only about half of what you observed in the SWOG subgroup
analysis.

MS. TULLY: That\'s very conservative.

DR. KELSON: I particularly have that in mind because we spent the whole
morning talking about an observation in a different stage of the same
disease using a biologic where relapse free survival was clearly
affected in one way or the other, but overall survival wasn\'t, and
overall survival is a much harder endpoint, you know.

DR. CHEEVER: It was my understanding from this morning\'s discussion \--
and correct me if I\'m wrong \-- that one of the problems with the
interferon trials is that everyone goes on interferon at some point in
time.

And I think you may find the same thing with vaccines, that following
relapse, a number of these patients will go on other vaccines at the
same time.

DR. KELSON: That would assume that they\'re effective.

DR. SOSMAN: I think that I\'m not so sure that we can say with staging
in 2002 that that many people will relapse in their regional nodes.
However, the patients who relapse will relapse systemically and almost
uniformly die of disease.

In those cases, we\'re now projecting seven, eight, nine years from now,
and while I think there were some very elegant comments about the lack
of movement in the field, we\'re hoping eight, nine years from now we
actually might have therapy for a subset for patients with metastatic
disease.

So I think it is a little concerning that we might change that outcome
and relapses may be salvaged way down the line.

DR. KELSON: That would certainly be a most desirable outcome in the
future, but the reason I ask this is the way I read it \-- and please
correct me if I\'m wrong \-- you\'re going to spend three to four years
accruing patients, and you don\'t plan to do your first analysis until
five years from the end of accrual, and that\'s nine years.

And, therefore, as you have designed your trial, we all, I think, would
be delighted to see changes over the next nine years. You actually
don\'t plan to do your analysis for the next nine years anyway. So I\'m
still not quite 100 percent sure why you wouldn\'t be looking at
survival under those circumstances.

DR. CHEEVER: Stuart, do you want to answer that?

MR. KROLL: My name is Stuart Kroll. I\'m the Director of Biostatistics
at Corixa.

I think we looked at the 57 percent difference that Tom was talking
about and thought that being that this was a selected subgroup, that
that would probably be too optimistic a difference.

And we also looked at the survival and felt that with this group where
everyone is staged that the survival also would be higher than what we
saw in the SWOG study, and given both of those facts, even though Tom
says a 30 percent difference in survival our study is adequate powered
for, a 30 percent difference in survival is a huge difference, and the
way we worked it out, we still think that we would want additional
follow-up for survival. So probably an additional two years, two or
three years after the five year point, and to make sure that we\'re
adequately powered for that survival endpoint.

CHAIRPERSON NERENSTONE: Dr. Albain.

DR. ALBAIN: I wanted to commend you for a very educational, interesting
presentation.

I wanted to change the subject a little bit. I find this very exciting
data and am just concerned that it\'s going to be ten years before, if
all goes well, that you will have an answer and would encourage us to
think about expanding your eligibility a bit more even so that you can
accrue more quickly because you mentioned this is 25 percent of the
population, but that\'s not the A2/C3 or A3/C2 \-- did I get it right
the first time? \-- A2/C3 subtype.

DR. CHEEVER: The A2/C3 would be half of that.

DR. ALBAIN: Right. So, in fact, I\'m not convinced you\'re going to
accrue as rapidly as you think you might in this very restricted
appropriate population for this type of study and would have no problem
with you expanding the eligibility a bit.

But could you comment on this long time?

DR. CHEEVER: John, may you or Walter could talk about accrual.

DR. THOMPSON: The history from the previous study, 9035, is that
patients began to enter treatment in 1992 and then accrual ceased in
1995. So the patients were accrued in that interval of years.

And the rate of accrual ramped up significantly toward the latter part
of the study.

DR. ALBAIN: That wasn\'t the A2/C3 group.

DR. THOMPSON: Well, you\'re right, but that was all patients, and the
A2/C3 group is 58 percent of the entire group that we\'ll enter on the
study. So if you project a higher rate of accrual, the type of rate that
we saw toward the end of 9035, multiply that by 58 percent; that would
be the rate that we would have accrued in the mid-\'90s.

Now, with the increasing interest, the A2/C3 equation to this, I think
that interest in this trial and, hence, patients being referred for
consideration of this trial has to go up. I don\'t know how much. That
will remain to be seen, but I would predict that it would go up
substantially.

DR. SOSMAN: Dr. Cheever speaks obviously more as a representative of
Corixa. I think your point is well taken in terms of expanding the
indications for this trial. There are a lot of issues with that, but we
don\'t have a cooperative group trial for any of those patients.

I think that this trial hopefully will \-- SWOG 9035 was a single group
study without intergroup support, and this trial will hopefully and
almost has to be a multi-group trial.

And I think there is interest in the other cooperative groups. We have
talked a lot about this, and I think there is an interest in this.

CHAIRPERSON NERENSTONE: Dr. Nelson

DR. NELSON: I have a follow-up of that question. I\'m trying to make
sure I get the twos and the threes and the ABCs correct.

But given the discussion this morning, why not establish a sort of
parallel track with much the same design, including what looks to me
under the new classification 2C, 3B, 3C, which would be basically those
who would refuse INTRON and then be eligible for enrollment into a trial
designed much in this same way as a second population, not lumped
together, but then analyzed separately.

DR. THOMPSON: You mean the node positive? Are you referring to the \--

DR. NELSON: Well, I guess I\'m following up. If, if, big \"if,\" the
conclusion was that someone who does not want to receive interferon
could be eligible for a vaccine trial, you\'ve excluded the groups that
are currently eligible for interferon. So if you don\'t \-- I\'m not
saying put them together for the purpose of analysis, but allow
enrollment for individuals who then fit the new classification two and
three that would be eligible, but are yet still HLA-A2/C3 positive.
Would that then give you more and allow you to draw some conclusions
that could address that previous question?

DR. THOMPSON: Well, we\'re going to bring up the slide that shows the
new AJCC staging system again, and one of the powerful features of this
is that it allows us to predict very accurately the outcome, the relapse
free survival of patients in each category, and we\'re going to see in a
minute here the categorization of the patients who are in 1A, that is,
that they have a single node that was clinically occult.

DR. NELSON: But I\'m basically asking why not include those who refuse
interferon in your trial rather than those who just aren\'t eligible for
the current approved indication for interferon.

DR. THOMPSON: Well, maybe I\'m not understanding, but one proposal would
be to include these patients in the current study that Dr. Cheever has
just presented because they have a similar risk of relapse as the
patients who are in Stage II.

DR. NELSON: Well, I saw that for 3A, but I guess, again, this is not my
field. So I\'m asking in the sense as a \-- there are others who would
have 3B classifications that \--

DR. THOMPSON: Well \--

DR. NELSON: Am I asking a clear question? Maybe you should restate it.

DR. URBA: I think the answer to that is the goal is to replicate 9035,
and getting too far away from that changes the interpretation of the
study, changes the patient make-up, and then the real question and the
hypothesis behind this study is to repeat what was done before as
closely as possible, to try and make sure that you don\'t make any
mistakes in development of this vaccine so that \--

DR. NELSON: Right. I understand.

DR. URBA: \-- if it works as effectively \--

DR. NELSON: I\'m suggesting do that plus more, is what I\'m suggesting.

DR. URBA: Well, there\'s no question that one would be interested in
looking at what Melacine does in other stages outside of this defined
study. I wouldn\'t argue that.

I think what you heard from the experts sitting over here was permission
to do things like Melacine in those patients if they refuse interferon.

I would agree with the panel members from this morning that the answer
is, yes, we should make that studies available.

Now, if you\'re talking about a separate Phase 2 study or something
asking a different question and interferon refuseniks, I would agree.

DR. CHEEVER: I would say there are two competing factors. One is the one
that replicates SWOG 9035 as closely as possible, but the other is the
possibility of entering interferon refuseniks, if you will call them
that, and that is a new concept which I think we really have to wait the
FDA\'s final opinion as to what transpired this morning and the final
conclusion before we can inculcate those ideas, I think, into our
thinking and future plans.

DR. SOSMAN: I think, you know, just sort of to add to them and to add
what Dr. Fleming and the other statisticians have said, I think it would
be a real mistake to under power the group that made up 9035. So you
could add a variety of other groups. I\'m not saying that that \-- you
know, there are many issues with it, but if whatever study you design,
power your study so that the group that were on 9035 are adequate,
whether there\'s 700 or so, so that you can do the study and you don\'t
lose the significance in that group.

And one of your primary objectives is that group has a better outcome.
That way you won\'t have diluted it with patients who may have a
different immune response. There\'s so little we know and so many
variables that we don\'t want to make that mistake, but there are many
ways around it.

CHAIRPERSON NERENSTONE: We do have some time constraints, and I think
maybe if the sponsor would like one of you to answer the question so
that we can continue on because we\'re going to lose some of our
committee members to flight problems.

Dr. George.

DR. GEORGE: I would like, first of all, to cast my vote with those who
were suggesting that this trial should be designed at least partly with
overall survival as the primary endpoint. I think that would be a very
important thing to do.

The second part of my comments had to do with eligibility though. You
stated numerous times that the goal is to replicate 9035, and what I
think you mean by that is you\'re doing a confirmatory trial of a
positive subgroup analysis in these A2/C3 patients, not really to
replicate entirely 9035.

And my point about this is you could also view this as you have an
opportunity for a confirmatory trial of a negative subgroup analysis in
the other patients. That is, how do you know that the vaccine doesn\'t
work in these other patients? You had this subgroup analysis that says
it\'s positive in one subgroup. You have the same kind of analysis
saying it looks negative in the other, but is there some disadvantage
with broadening the eligibility requirements to include those patients,
not to change the numbers with respect to how many you need in the A2/C3
group, but why not do the other?

DR. CHEEVER: We\'ll have Dr. Jacobs answer your question.

DR. JACOBS: Hi. I\'m Cindy Jacobs.

That\'s a good point. In fact, when we discussed with FDA SWOG 9035, the
approval of that trial, the main problem was that the effect we saw in
A2/C3, although it had been confirmed in the SWOG trial from Mitchell\'s
prior data, it was the subgroup analysis, and that\'s why that
accelerated approval was not an option.

For us then as a company to go and do another eight to ten year trial,
we need to have a study that we look at the intent to treat population
of that entire study to confirm for approval those A2/C3 positive
patients.

DR. SIEGEL: It is worth noting that the agency has permitted and does
permit trials to be designed in which the primary analysis is based on a
subset. In a case such as this, where the prior data suggests efficacy
in a subset, if your trial is designed as it already is to assess
efficacy in the subset, enrolling patients who don\'t belong in that
subset on the same trial would not force you to have that larger set as
a primary analysis. We have in the past and do accommodate that sort of
approach.

DR. GEORGE: Well, just to be clear, I wasn\'t suggesting any change from
that primary focus, but broadening the patients \-- that is, still the
main focus would be in this A2/C3 group. So just a comment.

Also, the other with respect to eligibility, I also don\'t see why you
can\'t broaden it with respect to some of these other stages because of
the new definition. You\'ve been toying with that, but it seems to me it
would be better to include them even if your primary hypothesis focused
on a smaller group.

DR. CHEEVER: Okay. Thank you.

DR. JACOBS: If you\'re referring to more general Stage III and Stage IV,
we have done or RIBI has done trials with Melacine, including INTRON-A
compared to INTRON-A plus Melacine, and those studies did not show or
indicate any benefit or synergistic effect of Melacine with INTRON-A or
in Stage III to date.

So really what we\'ve seen is in Stage II patients, and that\'s why for
us as a company to move forward for regulatory approval to focus on that
patient population for this next trial.

CHAIRPERSON NERENSTONE: Dr. Brawley

DR. BRAWLEY: Three very quick points. I understand the point to expand
\-- well, first off, if more than three percent of melanoma patients
went on the clinical trials, you could accrue a lot faster and finish
this a lot faster. That just is a parenthetical remark.

I also understand that if you increase the stages available to the
clinical trial, you\'re probably asking a different question, at least a
different biological question.

So I understand why you want to stay with this low stage group of
individuals.

And I also have made quite a career criticizing people for doing subset
analysis based on race. So I\'m not going to criticize you for not
wanting to do a subset analysis based on something else now.

The one comment that I\'d really like to make for the record in terms of
overall survival versus disease free survival, when you have a treatment
that has a very, very small impingement upon quality of life, and I
really don\'t think you\'re \-- except for some side effects at the
injection site, I don\'t think you\'re interfering with the quality of
life of these patients. Disease free survival actually to me becomes a
much more important measurement.

You know, in the INTRON-A discussion where you\'re giving people really,
really harsh treatment, I\'m just more interested in overall survival
versus disease free survival, but if you don\'t push overall survival
with a treatment that has very little effect on quality of life, but do
improve disease free survival, to me you win on qualify of life points.

Did I blur that or did you understand what I was saying?

DR. CHEEVER: I understand that, and I appreciate your comment.

Do you want to comment, John?

DR. THOMPSON: Well, I would just second your statement regarding the
toxicity of this regimen. I think my colleagues here will back this up,
that the side effects of this vaccine protocol compared to other things
that have been discussed this morning is fairly mild, injection site
reactions primarily.

And I think that because of that I agree with your point that disease
free survival assumed a greater importance, and perhaps that is another
reason to look at that as the primary endpoint.

CHAIRPERSON NERENSTONE: Dr. Sledge.

DR. SLEDGE: I actually don\'t have any questions, just one comment. You
know, listening here, this entire conversation is devolving rather than
evolving, and that is to say we started out with a very general, almost
philosophical question and now we\'re going into the \"nitpicky\" parts
of designing your trial for you, for which I think this Committee should
apologize to you.

There is probably nothing more dangerous than a group of non-experts
trying to pretend that they know how to design a melanoma trial. So I
guess my question would be either of you or the agency, I mean, is there
some general important question that you want to hear from us rather
than us writing your inclusion and exclusion criteria for you?

(Laughter.)

DR. SIEGEL: Yeah, you have printed questions, and I think from our
perspective, you know, Question 3 which asks \-- because this trial
presumably will come back to this Committee. You know, fortunately most
of you will have rotated off and won\'t have to stand behind your
decision.

(Laughter.)

DR. SIEGEL: We\'ve had this experience before, and that Committee is
going to come back and say, \"Well, geez, why didn\'t you bring us a
trial with this endpoint when it clearly should have been with that
endpoint?\" or, \"why did you bring us a trial with this entry criteria
when it clearly should have been that entry criteria?

Well, ultimately, you know, I think companies and the FDA find it useful
to get input before, you know, putting in seven or ten years and tens of
millions of dollars and the sacrifices of hundreds of patients, of their
time and effort and concerns into a trial to try to make sure that it is
going to satisfy what not only those of us in the agency think would be
appropriate, but what our expert advisors think would be appropriate.

So the questions do kind of focus on the areas that we think are most
important, and I think the questions to you are closely parallel to the
same questions. The inclusion of N1 patients, the nature of the
endpoint.

DR. CHEEVER: We greatly appreciate your comments. As a company, there
are certainly some people within our group that are hesitant to initiate
a trial that will take years. In order to initiate that trial, we really
need to make sure that the is consensus, that it\'s the correct trial,
and that there is a clear path forward for regulatory approval if the
study turns out to be positive as we predict that it will.

CHAIRPERSON NERENSTONE: Dr. Vanderpool.

DR. VANDERPOOL: Given some of my comments this morning, Jay, I may be
rotated off this Committee after one meeting.

(Laughter.)

DR. VANDERPOOL: We are being asked to confirm whether the \-- we\'re
being consulted for advice concerning appropriate patient population to
confirm the first pivotal trial results. I can understand, on the one
hand, why you want to really control this, keep this trial to Stage II
melanoma, because that\'s where the problem was, and you want to get on
with the program and see if you can have an effective drug.

I think the questions we have \-- and I certainly entirely agree with
Dr. Sledge that we can\'t \-- I certainly have no wisdom as to how to
design trials \-- but I would hope that either interferon is beginning
to show interest in doing research on Stage II melanoma or that, given
the past success of your dealing with these patients with these
particular A2/C3 genetic profiles, that you might be able to do
something that the interferon trials are doing.

In other words, I can see why these trials need to be cleanly separated
out in their own worlds, but at the same time would it be possible for
the sake of faster drug development to have some crossovers between
interferon, on the one hand, and your treatments, on the other?

That\'s my only open question.

DR. SOSMAN: Referring to that and a number of other comments, there\'s
been lots of discussion with ECOG, and one of the thoughts has been that
the A2/C3 negative patients would go on the ECOG 1697 study because SWOG
is not active in that trial, and they very badly need our involvement.

At the same time, ECOG would enroll their A2/C3 patients onto this trial
and I think that would benefit everybody.

DR. CHEEVER: One last comment, to make sure it\'s clear that interferon
in the standard high dose as proven to be effective is not currently
being tested in this disease category by any of the cooperative groups.

DR. VANDERPOOL: I understand that. I mean, my question is given the
effectiveness on the later stages, I didn\'t know whether Dr. Siegel
would have any comment as to whether the makers of interferon are also
interested in this earlier stage of melanoma or not.

CHAIRPERSON NERENSTONE: Dr. Carpenter.

DR. CARPENTER: Since there\'s been so much discussion about the choice
of endpoints and it\'s inevitable that depending on who the committee is
that this comes to in however many years, that there may still be
discussion, and since it won\'t apparently cost you any more patients,
if you can structure this so that both overall and relapse free or
disease free survival are primary endpoints, you would be prepared at
that point to deal with the agency and with the Committee no matter
which way they come down on the question.

And it would be relatively easy at this point to incorporate that design
point in.

CHAIRPERSON NERENSTONE: What I\'d like to do now is turn to the
questions because that will engender a little bit more discussion.

The first question, skipping all the way down towards the end: please
comment on the adequacy of the proposed development plan based on SWOG
9035 and the proposed trial to support the approval of Melacine for the
adjuvant treatment of melanoma in this defined population, the HLA-A2
and/or HLA-C3 phenotype and Stage IA and IB melanoma.

Further discussions to that specific point? Dr. Nelson?

DR. NELSON: I have a question. Do you think that the stage is more
important or the HLA type is more important as the underlying factor
relative to efficacy, not that I would design it any differently at this
stage?

DR. CHEEVER: I mean, we think that both are important, that the vaccine
will work best against patients with small tumor burden, but we also
have the test evidence that it works in A2/C3 positive patients. I think
they\'re both important.

DR. KEEGAN: Could I just clarify the intent with the question? The
proposal is really one of given all of the data available with Melacine,
including the two randomized controlled trials in metastatic disease
that failed to meet their primary and secondary endpoints, a very
intriguing finding on the subset analysis of one trial and one
additional confirmatory trial looking to confirm that subset finding.

Does that as an approach look like an acceptable development plan to
lead towards licensure? And that\'s really the essence of the question.
So I want to make sure I clarified that as you discussed that.

CHAIRPERSON NERENSTONE: Well, just a point of clarification then.
Assuming that this subset secondary trial was positive, would the
indication then be broad or would it only be in the HLA subtypes that
are being evaluated here?

DR. KEEGAN: I think it would be limited to the subjects that were
studied in which the positive effects were found. So, yes, I think it
would be limited to those HLA subtypes.

CHAIRPERSON NERENSTONE: And correct me if I\'m wrong, but I believe that
in the analysis there were other HLA subtypes that also looked
promising. The effect was strongest in these two subtypes, but there
were two subtypes that looked like they were positive, but there
weren\'t enough patients to make it statistically significant.

And do you really want to eliminate those from your study group so that
those from your study group so that those patients are not going to be
treated?

DR. CHEEVER: Mitchell predicted \-- pardon me. Go ahead.

DR. SOSMAN: There were two analyses, and one led to the next, and
that\'s exactly how Malcolm Mitchell initially did that.

The initial analysis included \-- the initial analysis centered on the
five and HLA antigens, serologically typed, and of which really two are
very infrequently expressed in the public in melanoma patients.

E44 is not infrequently. It\'s about 25 percent of patients, but we saw
no relationship at all with that separately, and since that really
limited the number of patients and was a complex, hard to understand,
and we really tried fairly simply. We didn\'t do complicated statistical
analysis pulling one HLA type out and looking at the analysis. We simply
looked at A2/C3 after we looked at each one independently, and that
seemed like the simplest way to develop it and to try to support the
finding.

CHAIRPERSON NERENSTONE: Dr. Kelson.

DR. KELSON: This may be semantics. I\'m not really sure. The way I was
looking at this is they have a hypothesis generating trial from a subset
analysis. They\'re not confirming really that.

The trial that they\'re going to do is a pivotal trial in a defined
subset, it will be the registration trial, and the supporting evidence
for this single pivotal trial would be the retrospective sort of look at
the subset from the main trial.

So the question to me sort of is a single pivotal trial with supporting
evidence retrospectively adequate for approval. I mean that would be how
I would sort of think of it.

DR. KEEGAN: Yes, I think you have the sense of it.

DR. SIEGEL: Exactly. That\'s the question, and that is, you know \-- by
our standards that can be in some settings, but each setting has its own
nuances, but in many adjuvant settings the agent is also already
approved for treatment of widespread metastatic disease. In this
setting, you know, the issue of how strength \-- that exploratory
analysis was not entirely retrospective and it has some support from
Mitchell\'s observation. So it has its own nuances, and that was the \--

DR. KELSON: That\'s why I was asking for an overall survival because to
me, if you if you did a single trial prospectively designed based on a
very valid hypothesis, I agree. I think it\'s a very valid issue to look
at, and the overall survival was improved. There was no, you know,
relapse free and dah, dah, dah, dah, with supporting evidence from
another prospective trial, minimally toxic drug, boy, I would think that
would be very compelling.

I would like to hear overall survival personally.

CHAIRPERSON NERENSTONE: Seeing the nods around the room, and I know
people are worried about overall survival, the drug company is worried
because of secondary home run hits that have not yet been postulated as
what we\'re going to do in terms of metastatic melanoma.

I think a word to the wise is that overall survival is felt to be a very
strong indicator and one that you can take to the bank. Relapse free
survival is going to be much more problematic with any sitting ODAC.

Dr. Albain.

DR. ALBAIN: I was just going to say the same thing. Unless you could
come up with a placebo, then I think relapse free survival could be very
powerful in a single pivotal trial.

CHAIRPERSON NERENSTONE: Dr. Fleming.

DR. FLEMING: I\'ve been waiting to make some of these comments because
they relate to survival in Question 3, but Dr. Kelson has so beautifully
articulated my own thoughts that I\'m going to jump in and fold in my
answer to three into one.

My own sense about the answer to one is, in fact, very significantly
tied into whether the endpoint is recurrence free survival or survival,
and I think Dr. Brawley made a very relevant point that if you have a
very benign therapy in terms of its toxicity profile, one might set the
bar lower in terms of efficacy.

And even if relapse free survival doesn\'t reliably predict survival,
does it predict some type of quality of life benefit that because of the
low toxicity profile is still net benefit. My sense about that is it may
well, but then again, if that\'s what we\'re trying to prove here, I
have more reservations about not having two independent, well designed
confirmatory trials.

I am more concerned about the issue of subjectivity and potential bias
in an open label trial. As a result if one is proposing to do two such
studies, it might be from my perspective more acceptable, but I do find
the strategy the sponsor has put forward here as appropriate exactly for
the reasons Dr. Kelson indicated, if in fact survival is the endpoint.

And when we were talking about \-- at least Dr. Kroll was responding
from the sponsor\'s perspective about a reason to go with relapse free
survival instead of survival, and he made two very valid points. One is
even though the estimated effect was 57 percent reduction in relative
risk for survival in the very kind of trial we\'re trying to replicate,
one should be cautious about expecting too high a bar, and then I think
he also pointed out there may be fewer events than what had been seen in
the previous study.

My responses to that are first you\'re already being cautious, assuming
five to six years\' average follow-up. It\'s a three or four year
recruitment trial with five additional years. So we\'re probably more
along the lines of seven years\' follow-up. So I think you\'re probably
covered there.

The other is the way you did your calculations you were targeting
relapse free survival for an 80 versus 70 that corresponds to a 37 and a
half percent reduction in risk that will require an observed 28 percent
reduction in risk.

If you have an observed 30 percent reduction in risk in mortality, you
achieve statistical significance, and you\'re trying to replicate the
SWOG trial that, in fact, showed a larger reduction in risk in survival
than it did in relapse free survival.

So the argument that you want to not overshoot is the rational one, but
I could say that it\'s just as plausible that you\'re overshooting based
on relapse free survival if you believe your results. If you believe
that there, in fact, is substantial evidence in this subgroup for
benefits on both relapse free survival and survival.

As a result, I concur with the thought of being cautious, but it seems
that if you believe the data and assume that you could achieve even half
the level of estimated reduction that you achieved in the SWOG subgroup
analysis, you will have significance on an endpoint that then I would
accept.

If they show survival in this study, they will have one pivotal trial
where supportive evidence will be obtained from a subgroup analysis that
are notoriously unreliable, but it certainly could serve as supportive
evidence for a survival endpoint.

DR. SOSMAN: Just one point, and it isn\'t in counter to what you just
said, but the survival benefit was evaluated by Corixa after the data
sweep to see if \-- really just to look to see if the disease free
survival would equate with overall survival.

SWOG did not do that initially and weren\'t planning to, but SWOG
repeated all of the statistics to make sure that they were consistent
with what they had, and they looked again and saw the overall survival
benefit.

And what\'s interesting is that overall survival benefit was much less
significant earlier when the first analysis was done than in the later
analysis.

So as opposed to all of the discussion this morning about separation, at
least in this study it doesn\'t appear that there\'s a separation.

CHAIRPERSON NERENSTONE: We could go on to the second question, which is
a little bit different.

Comment on the acceptability of inclusion of patients with pathologic N1
disease. If acceptable given that the SWOG 9035 trial did not include
such subjects, please comment on whether there would be a requirement to
enroll a sufficient number of subjects with no involvement to assess for
size effect in this subset.

I sort of think this is getting back to what Dr. Sledge said was micro
management, and I don\'t know if other people have thoughts.

DR. SIEGEL: Well, I\'m trying to understand the question. So let me ask
to understand. The question says patients with micro nodal disease were
not included, but I gather from the presentation that diagnostic
procedures were different so that you anticipate that those patients may
have been there, but were less likely to have their microscopic disease
diagnosed.

So in part that\'s one of the questions, and part, I guess, this
question rests on the issue that this is a population that falls within
the category for which interferon efficacy was demonstrated.

Now, we have discussion from this issue this morning. It\'s a higher \--
well, it may not be a higher risk. It falls within the population that
was included in the study. So that raises the question as to whether
they are appropriate for a placebo controlled trial.

And I believe I understand form your data that one of the points that
you\'re making, however, is that whether by categorization or
classification, they fall into one category. Their prognosis is actually
a relatively favorable one with 70 percent five year survival not very
different from the other populations that you\'re including.

Am I getting the nuances of the issue here?

DR. THOMPSON: I think so. I think it\'s worth repeating that a
relatively small number of patients actually had sentinel lymph node
biopsy on the 9035 study, about 30 patients. So the remainder of the
patients were clinically staged, not pathologically staged.

Given the depth of the primaries, 1.5 to four millimeters, we could
predict that approximately 15 percent, 20 percent of those patients
would have had occult nodal metastases that would have been identified
by sentinel lymph node biopsy and would have fallen into the N1a
category in the new staging system, but we didn\'t have that methodology
at that time.

And then as a follow-up to your question, I think the important thing
about the new staging system is though it tends to segregate patients
out by prognosis differently than anatomic staging, so node positive if
they\'re in the N1a category actually have a risk five year relapse free
survival risk that\'s very similar \--

DR. SOSMAN: It won\'t go up.

DR. THOMPSON: I\'m sorry. I was just looking at it here and thinking
that everyone else can see it.

DR. CHEEVER: No, it\'s not up there.

DR. THOMPSON: But that\'s 69 percent, very similar to the risk
categories of the Stage II patients that are already being proposed for
the trial.

So although it seems a little bit discrepant in terms of anatomic
staging, in terms of risk taking, it\'s very consistent.

DR. SIEGEL: So you believe including those patients actually comes
closer to replicating what\'s logged in in the 90s than excluding them?

DR. THOMPSON: Well, I think from a biologic point of view having to do
with risk of recurrence as the question mark, it would be very
consistent to include those patients, and we have no reason to think
biologically that they would be different.

However, we could be missing something, some different biology that we
just are not aware of, but strictly on a recurrence risk basis, they
could fit in.

Then the question becomes because that is node positivity, does that
require a different control group and that would be an issue that I
think would be open for discussion.

CHAIRPERSON NERENSTONE: I think again I\'m going to take the Chair\'s
prerogative. On the basis of all the discussion we had today, I think
the feeling is if you wanted a no control arm even in those patients who
were offered interferon and the subgroup that it\'s licensed for, most
of use felt that even though there is some activity, it is not a home
run and, therefore, it is not unethical to have a placebo controlled or
no treatment control.

You just have to be careful what you wish for because at the end of the
day, you include these patients in your trial and your trial is
negative. If you don\'t have enough patients who are node negative, you
don\'t have enough power to stand up on your own in that subgroup.

You can\'t then come back and say, \"Well, it was still positive in the
node negative group,\" but the node positive group is the one that made
it not significant, and therefore, you want to come and have it licensed
for the node negative group.

So I don\'t think it matters to us who you want to include in your
group. You have to be able to analyze it and to justify that analysis
when you\'re done with the study.

DR. CHEEVER: Thank you very much.

CHAIRPERSON NERENSTONE: Dr. Vanderpool.

DR. VANDERPOOL: I second your comments enthusiastically. It seems to me,
just to summarize what I\'ve been hearing, that we are under two
imperatives. One is to do the trials right, but the other is to find
better treatments as soon as possible.

So if the trial base can be expanded to the effect of finding better
treatments for other types of patients as soon as possible, we\'d be for
that if it can be justified on the basis of good analysis.

CHAIRPERSON NERENSTONE: Dr. Nelson.

DR. NELSON: This may be a question more for the FDA folks than the
sponsor, but I mean, the history of innovation in medical care is that
often if you have something that\'s more preferable in terms of
decreased toxicity, that once it\'s approved for one indication, we use
it off label for other indications.

So from a policy point of view if one of the questions ultimately you
might want to answer would be the efficacy of this product in those with
more extensive disease, a higher tumor burden and the like, would you
lose that window of opportunity if you didn\'t do it now as opposed to
when it\'s approved for those with lower tumor burden to the point where
I could imagine after approval, let\'s say, six years from now instead
of ten years from now if you have good enrollment, off label use would
be such that any further trial to demonstrate efficacy from a policy
point of view would become impossible.

And so people with melanoma would be taking potentially an ineffective
vaccine based on toxicity and rejecting more toxic but more efficacious
alternatives potentially.

Is there precedent for that kind of thinking?

DR. SIEGEL: It\'s funny. When you started the question, I thought you
were going to say the exact same question, except about people with
different HLA classes instead of with more advanced disease.

There is a lot of precedent for us urging, as Dr. George\'s question
suggested earlier, companies to study broader populations because of
concern about off label use in those populations. As to whether we can
require a broader study within our regulations has to do with a lot of
complex issues, but in part whether the population that\'s being defined
represents a defined indication with a medical acceptance and scientific
rationale.

So you can\'t just, you know, out of the blue say, as we once add a
proposal, \"I\'m only going to study men with multiple sclerosis because
that\'s the only people based on the ten I\'ve treated already that
it\'s going to work in.\"

But I would say where we\'re talking about well defined disease stages
that are used to guide how patients are managed, that are used in
interferon therapy or whatever, that we are probably in a position where
we could talk with a company and say, \"Look. We would anticipate off
label use. We would anticipate difficulty studying more advanced
disease. We think it would be extremely wise in the interest of the
patients and the public health, and we would urge you to study more
advanced disease.\"

But if a company came back to us and said, \"Well, you know, we only
have so much money and interest, and we have reason to believe this is
where it\'s going to work,\" I doubt we have the authority or ability to
say, \"Well, you can\'t limit it this way if it is a well defined and
appropriate limitation,\" which I think is what we\'re looking at here.

DR. SOSMAN: I\'m speaking not as a representative of Corixa, but as a
representative of SWOG who have worked with Corixa, and this is a very
fragile association that we\'ve tried to develop with this data, and
this data came from SWOG, not from Corixa.

And I think that what we\'re trying to d is move forward so that in six
to eight years we have a therapy to offer patients that is beneficial.
Obviously that will give them a product that they can sell, and my
concern is that if we start pushing for much larger trials, this fragile
relationship will become more fragile and we will lose this opportunity
which is really a unique opportunity.

And I can tell you most of the people who were associated with this
study initially, except maybe some of the people at RIBI had a very open
mind, nearly skeptical mind about this, and so the data has come around
to convince us that we need to reproduce it.

And I don\'t think you\'ll have any problem convincing Corixa to allow
us to do a study in Stage III patients if they have a product they\'re
selling to Stage II patients.

Now, it\'s not the company\'s problem to convince medical oncologists to
do the right thing. It\'s medical oncologists\' problem to do the right
thing.

Thank you.

CHAIRPERSON NERENSTONE: I just have a question to FDA. Sort of a
different tact to get back to something that was asked before, as a
non-vaccine person what do you think about the problem of you have two
components to the vaccine? You have the melanoma lysate and you have the
detox. Is there any data that this is at all detox.?

DR. KEEGAN: I don\'t think we have data that would assure us that we
could rule out that it was detox. alone that was the active agent.

There are some data along the lines that I think you probably heard from
other people talking about other vaccines about responses to the
vaccines, immunologic responses, how responders do better than
nonresponders, but those are responder/nonresponder analyses. So
they\'re difficult to do much with.

But we don\'t have any trials, and I don\'t believe that Corixa has ever
conducted any that have segregated the affected of the adjuvant alone.

DR. CHEEVER: I mean, in general, all vaccines are given with adjuvants.
Antigens don\'t work by themselves unless you add adjuvants.

I\'m not aware of other vaccines where one has had to test the adjuvant
to prove that it doesn\'t work before one can go ahead and test the
vaccine. We\'ve all \-- you know, every kid has 20 vaccines. They all
have adjuvants. The adjuvants have not been tested for efficacy in and
of themselves.

DR. SIEGEL: Well, when you say adjuvants don\'t work by themselves,
it\'s worth noting that in this particular disease, melanoma, that
non-antigen specific immune modulators, whether you call them adjuvants
or not, but some people would call Interleukin-2 an adjuvant. Some
people might even call interferon in some settings an adjuvant.

In any case, they change the immune response in a non-antigen specific
way, and they do in different stages and different settings each have
activity in this disease.

The question you ask is a subpart of a broader question, which is when
somebody develops a combination therapy and shows it to be effective,
when do we require that they show the combination of two new agents, if
you will, offers something beyond the individual components of, you
know, each agent.

Do we require a factorial design with one or both of the individual
agents? And that is an extremely complex question that rests in
significant part not simply on empiric clinical data, but also on
preclinical and plausibility data for the combination.

And if there is a strongly plausible reason for studying the
combination, we will not strictly require showing that each component is
contributory, at least in the premarketing phase. Sometimes we go back
in post marketing.

Also it rests on the additive toxicity of the individual components, and
in part that\'s an answer to the question Dr. Nelson raised, too, in
terms of our leverage and what we do regarding off label use. If there
are important safety issues that we\'re concerned about in off label
use, we are more apt to take a more aggressive approach in terms of its
study.

I think the general anticipation here \-- I don\'t think we have
definitive information, but based on what we know to date is that we\'re
probably not looking at tremendous additional toxicity for adding the
vaccine part to the adjuvant part, and so that probably figures into the
equation.

But I\'m not saying I know what the right answer to that question is and
should we require or insist on or should this Committee insist on
receiving the adjuvant alone or, for that matter, the vaccine alone are
interesting questions.

CHAIRPERSON NERENSTONE: Dr. Fleming.

DR. SOSMAN: There is actually a precedent in vaccine therapy. Dr.
Wallach did a trial with viral oncolysate plus he used an adjuvant
versus the adjuvant plus vaccine.

There was no difference, and from that trial he basically thought the
data showed that the adjuvant alone worked, and we don\'t want to get
into that position.

And secondly, no one made Dr. Fleming and others go back and prove that
it was Levamisole that added to 5 FU, not that I want to say that this
data is as good, but many people after the 5 FU/Levamisole data said
that it wasn\'t the Levamisole, if I say correctly.

It\'s not an issue now, but I think in this case it would be an awful
lot of effort for a little bang.

DR. JACOBS: I guess as far as Corixa is concerned, we\'re looking at the
Melacine as a whole vaccine. We have no intention even if the adjuvant
suddenly miraculously did something to market that.

So at this time in the clinical development plan, we\'re really looking
at developing vaccines as a whole.

CHAIRPERSON NERENSTONE: Dr. Fleming.

DR. FLEMING: Before I get to my comment, just quickly to follow up on
that previous thought, it was an important question as to whether it was
the Levamisole in the 5 FU/Levamisole, and at least there was a 5,000
person meta analysis of previous FU trials that seemingly at least
provided some considerable suggestion it wasn\'t the 5 FU alone.

But moving ahead just to question number two, and I just wanted to
reinforce a little bit what Dr. Siegel and some others have said about
the potential of looking at additional patients at this point in time or
additional \-- a wider array of patients. I just want to say, first off,
I\'m very pleased to see the commitment by the sponsor and SWOG to
mounting this trial to determine whether or not this exploratory
subgroup effect is real.

And there always will be judgment as to how inclusive to make
eligibility criteria where making them more inclusive gives us more
generalizable conclusion, more timely enrollment.

The disadvantage though is if you truly believe that you have, in fact,
modifiers here so that these HLA subgroups and these subgroups of stages
are far and away the most likely to have the most favorable benefit to
risk. There\'s a rationale for doing what you are proposing to do.

And, again, in my view, it\'s your judgment as to how you want to play
off that generalizability against increased plausibility of effect in
your more targeted group.

If, in fact, you do go with the more restricted group, which by my
calculation I think might be ten to 12 percent of the overall population
because you\'re taking the 25 percent and cutting it in half by looking
at these HLA subgroups, I do think there is at least some wisdom to be
thinking about whether mounting additional concurrent studies either as
extensions of this study, but not part of the primary analysis or as
separate studies, would be something wise to do.

And I just go back , and you were talking about SWOG, and I\'ll just
talk about the wisdom that SWOG had in 1984 in the 5 FU/Levamisole
setting. They were building off of the North Central Group trial, and
there was, in fact, a decision made to concurrently study Stage III and
Stage II so that when the Stage III results were in and were as positive
as they were, there were data in hand that were placebo controlled for
Stage II that might have been very difficult to mount in the early 1990s
if that study hadn\'t been started in Stage II at that time.

And those data did, in fact, suggest that the effect was very different
in Stage II than Stage III.

I\'ll also point out that there was wisdom at SWOG in not believing the
subgroup analyses entirely from the North Central trial that showed that
all of the effect in the North Central trial of 5 FU/Levamisole was in
the female populations in the younger patients.

The subsequent trial confirmed that gender and age were, in fact,
modifiers, where in the larger, confirmatory trial almost all of the
effect was in the males and the older patients.

So we\'ve learned to be very cautious about subgroup analyses. I guess
the bottom line here is it really is your judgment. There is an
investment in resources to do the complementary groups outside of your
targeted population, where from the targeted population if we don\'t see
an effect, maybe those resources weren\'t well spent.

On the other hand, if we do have the success that you\'re hoping to have
in our targeted subgroup, by HLA subgroups and by state subgroups, it
will be very beneficial that we will have mounted studies over this
eight year period looking at broader populations because it might be
awfully difficult in the year 2010 to mount such studies.

CHAIRPERSON NERENSTONE: Dr. Blayney.

DR. BLAYNEY: Yes. I also think it\'s commendable that you\'re committing
to a seven year trial on behalf of your company. That\'s important.

I would like to echo, I think, what the Chair said in her comment a few
minutes ago, that in eight years when you come before this Committee if
the question is asked, is this a breakthrough medicine, and the answer
because of intervening developments may be no, that then the FDA is
going to make you go back and prove that the lysate was the important
part rather than the adjuvant.

So I think and for my money you ought to be able \-- I would put this
mix together and say it is biologically and scientifically plausible
that all of this is important for the effect and not make them go back,
you know, in eight years and say improve each part of the mix as the
important part.

Because it may be by that time one of those antigens that you showed on
the board is available and useful, and you may get stuck with having to
prove what was the active part of your thing.

So I think you would be advised to get a commitment in advance that this
is the important \-- that this comes as a package because other
companies have stumbled in this regard.

DR. VON ESCHEN: I\'d like to make a comment to this question about
contribution of the antigen and adjuvant. My name is Ken Von Eschen. I
have been involved in Melacine\'s clinical development since the turn of
the century actually.

(Laughter.)

DR. VON ESCHEN: I kind of joke. I was with the ole RIBI and immuno-chem.
when the first IND for Melacine was filed, and, Dr. Keegan, I believe
that was even before you were at the FDA. So I\'ve got you beat, Pat.

Just a couple of quick comments. We have conducted a series of
preclinical studies in a variety of animal species looking at the immune
response to melanoma antigens in animals treated with lysate, with
detox. or the complete vaccine. Categorically, animals treated with only
the adjuvant never make immune responses to melanoma antigens.

Secondly, the very first initial clinical trials of detox. were done
under a separate IND in the early 1980s in which the adjuvant was used
as intralesional therapy in patients with cutaneous melanoma.

Those studies, uncontrolled, always showed that detox. administered
intralesionally, while they may have had an effect on the single lesion
that was injected, had absolutely no effect on any systemic metastases
and objective responses.

Finally, some initial trials done by Dr. Malcolm Mitchell in which he
treated Stage IV patients with the lysate alone showed absolutely no
objective clinical responses.

I think as we debate this issue, it\'s important to remember those
baseline facts, and as we look at the future trial, as Dr. Cheever said,
we perceive or recognize Melacine as a total package of antigen plus
adjuvant as giving the necessary immune boost to elicit positive
responses in these patients.

Thanks.

DR. SOSMAN: I just wanted to add one thing. I\'m sure some of you
appreciate where Dr. Cheever comes form in terms of immunology and his
prior involvement in the field at University of Washington.

I think all of us are also committed to do a corollary study in these
patients so that we hopefully not only learn whether it works or not,
which is the ultimate, the only important question, but why or when or
how it works.

So there\'s going to be, if this trial is mounted, a lot of effort,
hopefully from the intergroup mechanism, to study patients
immunologically pre and post vaccine.

CHAIRPERSON NERENSTONE: Dr. Keegan, Dr. Siegel, do you have any other
questions, any other comments?

DR. SIEGEL: I guess I have a question regarding the observation that
there weren\'t responses to detox. alone intralesionally in distant
sites.

Were there in the same study then responses to detox. with tumor lysate
in other sites that were significantly different from those in detox.
alone?

DR. VON ESCHEN: Dr. Siegel, in those trials, only detox. was used. There
was no combination of detox. and lysate, and those studies were done
under an IND, and the number is 1888, which was detox. only.

DR. SIEGEL: You don\'t have any particular model or any particular \--
or advanced disease where you do see a different response or you have
seen, I should say, a different response of detox. plus lysate to detox.
alone?

DR. VON ESCHEN: We\'ve never done a controlled trial in advanced
patients with detox. by itself compared to the intact vaccine.

DR. SIEGEL: I, for one, have found this entire day quite intriguing,
stimulating, and also fatiguing. And I\'m very appreciative of the
efforts of all the presenters, of the Committee, the public
participants, and yourself, Madame Chairman.

I think our questions are very well addressed on these issues. We\'re
quite pleased. Thank you.

CHAIRPERSON NERENSTONE: Dr. Pelusi, do you have any comments?

(No response and laughter.)

CHAIRPERSON NERENSTONE: Okay. Well, I want to thank everybody, and we do
get to adjourn a little bit early.

Our next meeting will be June 6th. Thank you.

(Whereupon, at 4:16 p.m., the Advisory Committee meeting was concluded.)