UNITED
STATES OF AMERICA
FOOD
AND DRUG ADMINISTRATION
CENTER FOR DRUG
EVALUATION AND RESEARCH
ONCOLOGIC
DRUGS ADVISORY COMMITTEE
74th
MEETING
WEDNESDAY,
MARCH
12, 2003
The
Committee met at 8:00 a.m. in the Versailles Ballroom of the Holiday
Inn-Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Donna Przepiorka,
Chair, presiding.
PRESENT:
DONNA PRZEPIORKA, M.D., Ph.D. Chair
DOUGLAS W. BLAYNEY, M.D. Member
OTIS W. BRAWLEY, M.D. Member
JOHN T. CARPENTER, JR., M.D. Member
BRUCE D. CHESON, M.D. Member
THOMAS
FLEMING, Ph.D. Consultant
(Viking)
STEPHEN
L. GEORGE, Ph.D. Member
DAVID
P. KELSEN, M.D. Member
SCOTT
M. LIPPMAN, M.D. Member
SILVANA
MARTINO, D.O. Member
MUSA
MAYER, M.S. Patient
Representative
(Voting)
GEORGE
OHYE Acting
Industry
Representative
(Voting)
JODY
L. PELUSI, F.N.P., Ph.D. Consumer
Representative
GREGORY
H. REAMAN, M.D. Member
BRUCE
G. REDMAN, D.O. Member
SARAH
A. TAYLOR, M.D. Member
JOHANNA
CLIFFORD, M.S., RN, BSN Executive
Secretary
SPONSOR REPRESENTATIVES:
GORDON BRAY, M.D. Ligand
Pharmaceuticals
STEVEN HAMBURGER, Ph.D. Johnson
& Johnson
Pharmaceutical
FRANCINE FOSS, M.D. Consultant
to Ligand
SUSAN KROWN, M.D. Consultant
to Johnson &
Johnson
JAMES L'ITALIEN, M.D. Ligand
Pharmaceuticals
SURYA MOHANTY, Ph.D. Johnson
& Johnson
Pharmaceutical
JAMES PLUDA, M.D. MedImmune
Oncology
APRIL TEITELBAUM, M.D. Johnson
& Johnson
Pharmaceutical
ALEX ZUKIWSKI, M.D. Johnson
& Johnson
Pharmaceutical
FDA REPRESENTATIVES:
RAMZI DAGHER, M.D.
ANN FARRELL, M.D.
PATRICIA KEEGAN, M.D.
GEORGE MILLS, M.D.
RICHARD PAZDUR, M.D.
QIN RYAN, M.D.
GENEVIEVE SCHECHTER, M.D.
ROBERT TEMPLE, M.D.
KAREN WEISS, M.D.
GRANT WILLIAMS, M.D.
I-N-D-E-X
Agenda Item Page
Opening Remarks - Dr. Przepiorka 5
Conflict of Interest Statement - Ms. Clifford 5
Open Public Hearing
Katherine
McComas 8
Steven
Walker 9
Frank
Burroughs 18
Accelerated Approval Process 23
Dr.
Pazdur & Dr. Dagher
Sponsor Presentation - Dr. Hamburger 83
NDA
50-718 Doxil
Treatment
of Kaposi's sarcoma in AIDS
patients
with disease that has progressed
on
prior combination therapy or in patients
who
are intolerant to such therapy.
FDA Comments & ODAC Discussion - Dr. Redman 110
Conflict of Interest Statement - Ms. Clifford 133
Sponsor Presentation - Dr. Hamburger 136
NDA
50-718/S-006 Doxil
Treatment
of metastatic ovarian cancer in
patients
with disease that is refractory
to
both paclitaxel and platinum-based
chemotherapy
regimens.
FDA Comments & ODAC Discussion - Dr. Brawley 156
Afternoon Session
Open Public Hearing
Maryann
Napoli 184
Maryann
Pendergast 190
Agenda Item Page
Conflict of Interest Statement - Ms. Clifford 187
Sponsor Presentation - Drs. L'Italien & Bray 194
BLA
97-1325/STN 103767 Ontak
Treatment
of persistent or recurrent
cutaneous
T-cell lymphoma in patients
whose
malignant cells express the CD25
component
of the IL-2 receptor
FDA Comments & ODAC Discussion - Dr. Cheson 248
Conflict of Interest Statement - Ms. Clifford 266
Sponsor Presentation - Dr. Pluda 268
NDA
20-221/S-002 Ethyol
Reduction
in cumulative renal toxicity
associated
with repeated administration
of
cisplatin in patients with advanced
non-small
cell lung cancer.
FDA Comments & ODAC Discussion - Dr. Blayney 299
P-R-O-C-E-E-D-I-N-G-S
8:10
a.m.
CHAIR
PRZEPIORKA: On the record. Good morning.
Welcome to the 74th meeting of the Oncologic Drugs Advisory Committee. The member of this Committee sit as
consultants to the FDA. This is not a
decision making body. The topic of the
meeting for the next two days is actually to catch up on some of the
accelerated approvals that have gone on over the past 10 years. We have some interesting discussion not only
of the accelerated approvals process but some of the things that we have
accomplished in the past and need to revisit.
Let me start by asking Johanna Clifford to make the Conflict of Interest
Statement.
SECRETARY
CLIFFORD: The following announcement
addresses the conflict of interest issues with respect to this meeting and is
made a part of the record to preclude even the appearance of a conflict. To determine if any conflict exists, the
Agency has reviewed the submitted agenda for this meeting and all relevant
financial interests reported by the Committee participants.
The
Conflict of Interest statute prohibits special Government employees from
participating in matters that could affect their personal imputed
interests. However the Agency may grant
a waiver if the need for the individual service outweighs the conflict created
by the financial interest.
Accordingly
waivers have been granted to following individuals: Dr. Scott Lippman for serving on a
competitor's speaker's bureau for which he has received less than $10,001 and
for consulting for a competitor on an unrelated matter in which he receives
from $10,001 to $50,000 a year; Dr. Thomas Fleming for serving on a
competitor's data monitoring committee on an unrelated matter for which he
receives less than $10,000 a year; Dr. Douglas Blayney for owning stock in the
sponsor valued from $25,001 to $50,000; Dr. Sarah Taylor for owning stock in a
competitor worth less than $5,001. A
copy of these waivers may be obtained by submitting a written request to the
Agency's Freedom of Information Office, Room 12A-30 Parklawn Building.
In
addition, we would like to note that George Ohye, is participating in this
meeting as the Acting Industry Representative.
Mr. Ohye would like to disclose that he owns stock in the sponsor and in
three competitors. He receives
retirement pay from the sponsor. His
wife works for the sponsor. Within the
past year, he consulted for the sponsor.
In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participant should exclude himself or herself from such involvement and the
exclusion will be noted for the record.
With
respect to all other participants, we ask in the interest of fairness that all
persons making statements or presentations disclose any current or previous
financial involvement with any firm whose products they may wish to comment
upon.
CHAIR
PRZEPIORKA: Thank you. We would like to now go on to the open public
hearing. We'll start by talking about
the correspondence that has been received.
SECRETARY
CLIFFORD: Thank you. The FDA did receive letters with regard to
this issue. In interest of time however
they will not be read out loud. However
they are available at the desk in the lobby and have been forwarded to the
members for their review. These letters
will be placed as part of the meeting record.
CHAIR
PRZEPIORKA: Thank you. We have three speakers for the open public
hearing this morning. I would like to
call forward the first speaker, Katherine McComas.
MS.
McCOMAS: Good morning. My name is Katherine McComas. I'm an assistant professor at the University
of Maryland. I'm going to be conducting
some research today with your assistance.
It's a questionnaire called "Conflict of Interest in Federal
Advisory Committees." I will be
distributing this at a break time. I
would be grateful if sometime today before you leave that you would complete
the survey. It will take about 15
minutes and deposit it in a box marked "FDA Survey" in the
lobby. This research is being conducted
with collaboration of officials at the FDA.
Your participation is voluntary but we'd greatly appreciate if you would
assist us. It will help us to understand
more effectively how you understand and know about the Conflict of Interest
procedures that the FDA uses to monitor the real and potential conflicts of
interest of its advisory committee members.
If you have any questions, I will be here all day. I will also be out in the lobby. Thank you very much for your time. We greatly appreciate your assistance. Thank you.
CHAIR
PRZEPIORKA: The next speaker will be
Steve Walker from the Abigail Alliance for Better Access to Developmental
Drugs.
MR.
WALKER: Good morning. My name is Steve Walker. I have the exalted title of FDA Advisor to
the Abigail Alliance for Better Access to Developmental Drugs. Why I'm involved in this will become evident
during my presentation. I have no
affiliations with any pharmaceutical companies or anyone else involved in drug
development. I pay my own expenses and
I'm here today on my own dime. I would
like to talk about something that is in part related to the subject matter
today and also in part related to our entire approval process and to propose a
new idea to ODAC, the FDA and everyone in the room.
As
you will hear probably all day long, accelerated approval is a part of a
three-part process that was really intended since 1992 to make drug available
much more quickly. You can't really talk
about accelerated approval without talking about fast track and priority
review. For what cancer patients wanted
from this program and really expected to have happen especially after the
Modernization Act, we expected or hoped for support of accelerated approval by
both industry and the FDA, meaningful participation by industry, effective
communication, good trials, regulatory acceptance of surrogate endpoints,
realistic evaluations of risk-to benefit and clinical benefit, flexibility of
the FDA which is something cancer patients don't see enough of, sense of
urgency at the FDA which I think exists but at the institutional level may not,
timely approvals and meaningful and implementable Phase IV trials for
accelerated approval.
Just
real quickly from the prospective of a cancer patient advocate who has direct
experience over the past few years of how this system works, there has been
inconsistent support of accelerated approval.
We are not seeing enough drugs come out.
There has been meaningful participation by industry in all three of
those programs.
Insufficient
communication between FDA and industry, it's not always as open and real time
as it should be. Clinical trial design,
we're going to talk about that today.
Limited regulatory acceptance of surrogate endpoints is a fact. There has been limited acceptance of that and
too much emphasis on a overly restrictive definition of clinical benefit. There has been unrealistic risk versus
benefit evaluations for end-stage cancer patients.
There
continues to be a lack of flexibility at the FDA. At the institutional level, a sense of
urgency doesn't seem to be there. We've
had a few timely approvals and too many delayed approvals. We're going to hear more again about not only
the usefulness of these trials but how implementable they are. It's difficult to test a drug in randomized
and placebo-controlled trials after approval.
That's just a common sense problem.
Why
has it under performed? In our view,
we're relying too much on statistics and process instead of whether or not we
have a good drug and whether or not that drug represents best available care
for some population of patients. There's
an overemphasis on adverse effects. In
fact, we should be looking more at the adverse effect of not making a drug
available rather than the adverse effect of making it available in a lot of
cases.
We
have failed to recognize at the technical level the right of Americans to
decide how they want to try to live.
That's a big problem for cancer patients by the way. We have as a result a pantheon of approval
authorities that cancer patients look at as not having worked the way they
should have. We're not seeing enough
drugs come through the system. We have a
big translation problem.
What
we need is more acceptance and support for not just a letter but the spirit of
accelerated approval which was to start capturing these people that fall into
this huge health care gap each year.
Beyond approved treatments, we lose about 800,000 or 900,000 every year
to cancer and they have nowhere to go except clinical trials which are too
small and too restrictive.
The
standards should not be moved forward to
unattainable standards. They should be kept where they are or moved a
little bit back. Lower hurtles. We need to redefine clinical benefit to be
something more than just life extension because I have personal experience with
surrogate endpoints being definite clinical benefit.
Defer
more decision making to the physician and patient in the post-accelerated
approval setting. Hopefully, you will
solve the post-accelerated approval setting today. I don't know if you will but I hope you will
and recognize the urgent need for timely approvals not just timely reviews.
Our
message for today's meeting is we need Phase IV trials that tell us something
that we don't already know. Maybe that
is why it doesn't work for 90 percent of a patient population and does work for ten percent rather than proving that it does
work for ten percent.
Phase
IV clinical trials should be ethical and enrollable. From cancer patient's standpoint and from a
lot of practicing oncologists' standpoints, end -stage cancer patients
shouldn't be going into randomized placebo-controlled trials. The oncologists won't put them in those
trials. So you have a question of
whether or not they are enrollable at that point which they probably
aren't. It's going to be difficult to
enroll at trial.
There
is also a question of ethics. Challenges
with designing post-approval trials shouldn't be considered a problem with the
design of the trial all the time. It
should be considered a problem with policy and regulations, for example, the
definition of clinical end benefit.
Survival advantage is not the only meaningful clinical benefit. We need to have everybody in this room
thinking that these drugs need to be made available faster.
Moving
beyond it, we think that the two approval mechanism we have now are good
approval mechanisms. We think that full
approval needs to be the final goal for every drug that is approved in the
United States. We think there should be
Phase IV trials after accelerated approval but these two systems have left
hundreds of thousands of Americans beyond approved options in what I call a
health care gap. It is huge and I'm in
it with my wife. It is horrible to be
there. We need to fix it.
We
need a new tiered approval system that adds a restrictive form of approval
earlier in the process that is somewhat like a Treatment IND but is designed to
serve this unserved patient population with appropriate restrictions because
those investigational drugs represent best available care for those
patients. The first one, Tier One: New Initial Approval, would become a first
approval authority for new drugs for life-threatening diseases with unmet
needs. It would follow along to Tier Two
and Tier Three. Tier One and Tier Two
would still be optional approval mechanisms for sponsors to pursue. They would be required after receiving Tier
One to pursue the other two or at least full approval.
The
way this would work is that this would be based on limited evidence of safety
and activity from Phase I or Phase II trials.
The marketing would be restricted to patients with life-threatening
diseases, no approved treatment options and no reasonable access through
clinical trials or EAPs which by the way is the majority of people in that
health care gap. Informed consent would
be required because the drug hasn't been fully evaluated. The sponsors would be required to continue
diligent pursuit of higher tier approval.
There are a lot of details that have to be filled in. We thought about all of those and I'm sure
you're thinking about them right now but this will work.
This
is my wife. She is 47 years old.
We was diagnosed two years
ago. She has Stage IV colon cancer. In September of last year, she had
progressive disease in both lobes of her lungs, both lobes of her liver. She had extensive peritoneal implants. She had an extreme ascites problem requiring
paracentesis every week to remove five liters of fluid.
The
last drug that worked for her was the Saltz regimen. She had Saltz regimen, Xeloda, Oxaliplatin in
the registration trial. Then because we
had nowhere else to go and couldn't get into the ABX-EGF trial and we tried
twice, she went through irinotocan and Xeloda.
Her prior history did nothing but make her sick and her disease
progressed.
She
got into the single-agent Erbitux trial in September of last year. Two days after she started the trial, I asked
her if she needed paracentesis and she said no.
A week later, the fluid stopped accumulating. Two weeks later it was completely gone. At six weeks she had complete resolution of
peritoneal implants. She had complete
resolution of the disease in her right lung and she had reduction of the
disease everywhere else. Eventually she
reached stabile disease at about 70 percent reduction and tumor burden with CEA
of 8.4.
She
has since progressed and was taken off the study yesterday because after six
months of extremely good quality life she was skiing two weeks ago in
Utah. She was taken off study because of
progression in her liver only. We now
have a plan for it that we wouldn't have had six months ago.
My
message to you is if this drug was available the statistics for colon cancer
patients would change. The reason I know
that is because in our clinic where there are about 20 patients enrolled which
is a targeted patient population that the partial response rate is very high,
greater than 50 percent. It could be
much greater than that in this targeted population. I don't have the official data. I can't get it. We want the FDA to find out what's going on
with this trial and to act. If this is
an example of a drug that would be a good candidate for Tier One approval. That's it.
Any questions?
CHAIR
PRZEPIORKA: Thank you for your insights,
Mr. Walker. I just wanted to know. Will your slides be available on your
website?
MR.
WALKER: They can be, yes.
CHAIR
PRZEPIORKA: Thank you. Any other questions? Our next speaker is Mr. Frank Burroughs from
the Abigail Alliance for Better Access to Developmental Drugs.
MR.
BURROUGHS: Steve, thank you so much.
Steve Walker is the Abigail Alliance FDA Advisor and he has done a tremendous
job for us. Thanks, Steve, for
introducing our Tier One initiative.
It's a really important idea.
I've met some of you this morning that I know and that know the Abigail
Alliance. For those of you who don't
know me, I'm Frank Burroughs. I'm
President of the Abigail Alliance for Better Access to Developmental Drugs.
I
want to add a few things to what Steve said.
This is the logo for the Abigail Alliance for Better Access to
Developmental Drugs. Some of you know it
already. It's my daughter who died in
June 2001 after not being able to get access to EGFR targeted agents that had a
significant chance of saving her life.
If she was alive today, she still could not get those drugs. This is two years later.
We
have Abigail as our logo because the Abigail Alliance and what we are about is
about people. It's about tens of
thousands of people in our country that need a better chance. This is important what I'm talking
about. Abigail represents, our logo
represents tens of thousands of people who are dying of cancer and other life
threatening diseases that don't have earlier access to development drugs.
Every
agency in the Government or business or myself can be prone to not making
change. We like things the way they
are. It's working. It's our idea. For example, FAA, not FDA, had not made
changes since the 1950's in airline safety, we would be having 100 times the
number of commercial air crashes we have in this country every year. There has been a tremendous increase in air
travel. If FAA hadn't made changes, we'd
have 20,000 deaths a year in airplane crashes.
The FAA made changes.
Of
course the FDA over the years has made some tremendous changes. It's a fantastic agency. Don't get me wrong. But everybody, any of us, can make
changes. I urge that we look close at
Tier One approval, the concept we have here.
This
is Peter Hallinan. He's no longer with
us. He was denied access to cancer drugs
that could have helped his brain cancer but they weren't approved yet. He didn't qualify for a clinical trial. He couldn't get into the expanded access
programs that were available. He didn't
meet those criteria either. With Tier
One, Peter would have had a chance at life.
This is a solvable problem. Just
think about it, if it were you. What if
it were your wife or your daughter that had colon cancer, had neck cancer or
brain cancer and couldn't get developmental drugs that had a significant chance
of saving their lives.
I
think we can speed this process with Tier One approval without jeopardizing the
important review testing procedure.
That's important. We need to
field clinical trials as soon as possible.
We can do all this, move a drug through the proper approval and review
process but get drugs to people earlier.
This
is Johnny Clark. We lost Johnny in
November. He couldn't get EGFR
inhibitors that had a chance to save his life.
He's left two children and a wife.
No one was listening to him. No
one was giving him a chance. With Tier
One approval, we could approve these drugs earlier for people who have run out
of options like Johnny Clark, like Peter, like Abigail and tens of thousands of
other people.
Today
we have drugs that have been approved that are saving tens of thousands of
lives. Gleevac, Eloxatin, Herceptin and
I could go on and on. You know the drugs
that are saving tens of thousands of lives.
Those programs had expanded access programs but those expanded access
programs left tens of thousands of people by the side of the road. Some companies don't do expanded access
programs.
With
Tier One approval, we could get these drugs to people years earlier. We need to work together. We need to be bold. We need to think outside of the box. The real power here is not with me. It's not with anybody in this room
really. It's with the cancer patients
and the other people with life threatening illnesses. We need to help them better than we are. I want to thank you very much.
CHAIR
PRZEPIORKA: Before you leave the podium,
are there any questions for Mr. Burroughs?
Thank you, sir. Are there any
other speakers for the open public hearing?
Hearing none, let us move on to the next item of the agenda. Dr. Pazdur and Dr. Dagher will talk about the
accelerated approval process.
DR.
DAGHER: Good morning. Today I would like to summarize our
experience with accelerated approvals from Oncology products over the last
decade. Before summarizing past
experience, I would like to outline the purpose of this meeting of the Oncology
Drugs Advisory Committee which is three-fold:
(1) to review past accelerated approvals; (2) discuss the current
progress of associated Phase IV commitments; and (3) solicit input for
improving the accelerated approval process.
I
would like to point out that summary includes Oncology products approved in the
Center for Drug Evaluation and Research as well as the Center for
Biologics. As part of this presentation,
I will provide some background on accelerated approval regulations, approvals
based on control trials lacking a concurrent comparator, mostly single arm
studies and those based on randomized trials.
A
summary of accelerated approvals ultimately converted to full approval will be
provided. I will complete the
presentation with a list of issues we would like the Committee members to keep
in mind during the individual sponsor presentations. Finally, Dr. Pazdur will introduce some
general issues about the accelerated approval program as a whole. These will also be presented to the Committee
tomorrow in the form of questions for discussions after all the sponsor presentations
have been completed.
Nineteen
NDAs or Biologic applications for new treatment indications in Oncology have
been approved involving 16 different products.
Some of these indications were approved within 18 months of issuing
invitations to this meeting and will not be presented by individual sponsors as
they are too recent for a discussion of the status of Phase IV
commitments. An additional four
indications have been converted to full approval. They will be presented by individual sponsors
over the next two days.
In
reviewing the regulatory background, please keep in mind that reference to a
drug also includes biologic products. In
1992, Subpart H was added to the NDA regulations allowing accelerated approval
for diseases that are serious or life-threatening where the drug appears to
provide benefit over available therapy.
Approval will be based on a drug's effect on a surrogate endpoint that
is reasonably likely to predict clinical benefit or on the basis of an effect
on a clinical benefit other than survival.
Approval
will be subject to the requirement that the applicant study the drug further to
verify and describe its benefit where there is uncertainty as to the
relationship of the surrogate endpoint to clinical benefit or of the observed
benefit to ultimate outcome. Post marketing
studies would usually be studies underway to demonstrate that treatment with a
drug is associated with clinical benefit.
The
regulations state that the applicant shall carry out such studies with due
diligence. If an applicant fails to
perform confirmatory studies with due diligence, the Code of Federal
Regulations describes a mechanism for removing the drug from the market.
In
general, we have considered an effect on survival or patient symptoms as
evidence of clinical benefit. Objective
Response Rate and Time to Progression have generally been viewed as surrogates
reasonably likely to predict clinical benefit.
In some circumstances where relatively non-toxic products are being
evaluated such as hormonal therapies for breast cancer and some biologic
products, Response Rates have been accepted as evidence of benefit. In the setting of hematologic malignancies, ?- responses have been accepted as clinically
meaningful.
This
slide and the following two slides summarize the approvals based on control
trials without a concurrent comparator.
As I mentioned, these are mostly single arm studies and in some
instances there are studies where two different dose levels were being tested.
In
1995, Liposomal doxorubicin was approved for the second line treatment of
Kaposi's Sarcoma based on response rate in a single open label study. In 1996, Amifostine was approved to reduce
renal toxicity associated with Cisplatin administration in advanced non-small
cell lung cancer (NSCLC) based on results of a Phase II study. Docetaxel was approved for the second line
treatment of breast cancer based on response rate measured in six United States
and three Japanese trials.
Irinotocan
was approved for the second line treatment of colon-rectal cancer based on
response rate measured in three single agent studies using a weekly dosage
schedule. In 1998 Capecitabine was
approved for the treatment of refractory breast cancer based on objective
response in a single Phase II study of patients who had failed prior Paclitaxel
therapy.
In
1999, Liposomal doxorubicin was approved for the treatment of refractory
ovarian cancer based on response rate in three single arm studies of women with
metastatic disease most of whom had failed both Paclitaxel and platinum-based
regimens. Temozolomide was approved
based on the results of a single arm trial in patients with relapsed anaplastic
astrocytoma who had failed radiation therapy and many of whom had also received
prior chemotherapy.
Denileukin
diftitox was approved for the treatment of patients with persistent recurrent
cutaneous T-cell lymphoma based on two arm study. Although analyzed, the trial evaluated to
different dose levels of this product without a control arm and is hence listed
in this category. In the year 2000,
Gemtuzumab ozogamycin was approved for the second line treatment of AML in the
elderly patients based on hematologic response in three single arm trials.
In
2001, Alemtuzumab was approved based on response rate and duration of response
in one single arm study and two additional supportive non-comparative
studies. Imatinib mesylate was approved
for the treatment of chronic myelogenous leukemia in blast crisis accelerated
phase or chronic phase after Interferon failure based on hematologic response
in three single arm trials conducted in patients with Philadelphia chromosome
positive disease.
The
approval for gastrointestinal stromal tumors was based on objective response
rate in a single two arm study. Although
many patients in this trial had not received prior chemotherapy, this was a
population with metastatic or unresectable disease where chemotherapy has a
less than five percent response rate.
Moving
on to accelerated approvals based on randomized studies, Dexrazonxane was
approved in 1995 for the reduction of cardiomyopathy associated with
Doxorubicin administration based on three prospective randomized trials in
which patients with breast cancer received a Doxorubicin containing regiment
with Dexrazoxane or placebo. Left
ventricular ejection fraction and the incidence of congestive heart failure
were primary endpoints.
In
1999, Liposomal cytarabine was approved for the intrathecal treatment of
Lymphomatous meningitis based on cytologic response in a comparative trial of
Liposomal cytarabine versus cytarabine in patients with lymphoma. Supportive studies were conducted in patients
with leukemia or solid tumors.
Celecoxib
was approved for the reduction of adenomatous polyps based on a randomized
double blind placebo control study in patients with familial adenomatous
polyposis. In 2002, Ibritumomab tiuxetan
was approved for the treatment of relapsed/refractory low grade follicular
non-Hodgkins lymphoma based on an evaluation of response in a randomized trial
comparing Ibritumomab tiuxeten to
Rituximab.
Oxaliplatin
was approved for use in combination with 5-FU Leucovorin based on a randomized
three arm study. Oxaliplatin combined
with Infusional 5-FU Leucovorin versus
5-FU Leucovorin alone versus single agent Oxaliplatin in patients with advanced
colorectal cancer refractory to first line treatment with Irinotocan and 5-FU
Leucovorin. Approval was based on
response rate and in interim analysis of time to radiographic progression.
Anastrozole
was evaluated in a randomized double
blind study comparing Tamoxifen alone, Anastrozole alone and Anastrozole in
combination with Tamoxifen as adjament treatment of post menopausal women with
breast cancer with disease free survival as a primary endpoint. Finally Imatinib mesylate was approved for
the treatment of newly diagnosed patients with chronic myelogenous leukemia
based on time to progression in a randomized trial of the Imatinib versus
Interferon.
If
we examine the endpoints evaluated, we can conclude that in the setting of
controlled trials without a concurrent comparator and in only refractory or
relapsed patients, objective response rate was the main endpoint of interest. In the randomized setting a variety of
endpoints from cytologic response to reduction in number of polyps were evaluated
based on the indication being sought.
You
may wonder why improvement in disease free survival or reduction in the
incidence of congestive heart failure would not be adequate for full approval
as opposed to accelerated approval. In
the regulatory background, I mentioned that when there's uncertainty as to the
relationship between benefit and ultimate outcome, the sponsor would be
required to study the drug further.
In
the case of products used for protection from cytotoxicity of cancer agents, uncertainty
as to possible existence of the tumor protective effect would exist. Hence although incidence of renal toxicity or
cardiac toxicity was evaluated in the case of Amifostine and Dexrazoxane
respectively, uncertainty about the possibility of a tumor protective effect
necessitated approval under Subpart H.
In
the case of Anastrozole although disease free survival was evaluated, patients
had received only a median of 31 months of a planned 60 months of
treatment. Hence uncertainty about
ultimate outcome necessitated approval under Subpart H with follow-up of the
same study as a Phase IV commitment.
Similarly, the approval of Imatinib for the first line treatment of CML
was based primarily on longer time to accelerated phase or blast crisis with
Imatinib treatment and was supported by hematologic cytogenetic response. Confirmatory evidence of benefit would be
provided by evaluation of time to accelerated phase or blast crisis and
survival after a longer duration of follow-up.
I
mentioned earlier that of the 19 indications of Subpart H, four have been
subsequently granted for approval. These
are listed here. Docetaxel received
approval based on a randomized trial comparing Docetaxel to Mitomycin
vinblastine and supportive evidence from a second randomized trial where
Docetaxel was compared to Doxorubicin in patients with metastatic breast
cancer.
In
the case of Irinotocan, conversion to full approval was based on two large
European trials in patients which failed first line treatment with 5-FU, a
population less refractory than that examined in the accelerated approval
setting. In the case of Capecitabine,
the confirmatory Phase III randomized study evaluated the
Capecitabine-Docetaxel combination versus Docetaxel alone in patients with
advanced breast cancer who had failed prior Anthrocycline. Again it was a population less refractory
than that examined in the accelerated approval setting. In the case of Dexrazoxane, we should point
out that a planned confirmatory trial was under way at the time of accelerated
approval. This was not utilized for full
approval.
Although
confirmatory trials were underway in these incidences at the time of
accelerated approval in any indications that have not been converted to full
approval, we have seen that approvals granted early in the history of the
program were not usually associated with on-going trials. Whereas in the last two years, confirmatory
studies have been underway at the time of approval in many instances.
Over
the next two days, the status of Phase IV commitments for the following
indications will be presented: Liposomal doxorubicin for Kaposi's sarcoma;
Liposomal doxorubicin for metastatic ovarian cancer; Denileukin diftitox for
cutaneous T-cell lymphoma; Amifostine for the renal toxicity associated with
Cisplatin use in non-small cell lung cancer patients; Gemtuzumab ozogamycin for
AML; Liposomal cytarabine for Lymphomatous meningitis; Celecoxib for familial
adenomatous polyposis; and Temozolomide for refractory Anaplastic astrocytoma.
As
you listen to these individual presentations, please keep the following in mind
regarding planned or on-going trials.
For an on-going trial, has accrual been satisfactory? If not, what strategies can be used to
address this issue? Have changing
circumstances such as a change in medical practice impeded the conduct of a
planned or initiated trial? If so, what
alternative designs should be contemplated?
At this point, I would like to turn things over Dr. Pazdur who will
introduce some more general concepts regarding the accelerated approval program
in Oncology.
DR.
PAZDUR: I would like discuss three areas
of Oncology Accelerated Approvals the first of which is the division's premise
that these confirmatory trials are an integral part of a comprehensive drug
development plan. Accelerated approval
does not end with the approval of the drug.
Hence the confirmatory trial should be discussed with the division early
in the development process and be an inherent part of the total drug
development strategy.
Secondly, I would like to discuss
that patient population examined in confirmatory trials. Frequently the division has allowed clinical
benefit to be demonstrated in less refractory earlier stages of the disease than
studied during the accelerated approval.
Lastly I would like to comment on the merits of different trial designs
specifically single arm versus randomized trials to obtain accelerated
approval.
The
preamble to the accelerated approval regulations comment that
"Post-marketing studies would usually be underway" at the time of
accelerated approval. Although we have
not insisted that post-marketing confirmatory trials be underway which may
potentially delay drugs to patients with life-threatening diseases, the
division believes that these studies need to be carefully planned and discussed
with the division early in the development plan preferably at or before the end
of Phase II meetings. There needs to be
continuous dialogue during the conduct of these confirmatory trials and
strategies in place for alternatives if they fail.
The
division envisions that a sponsor is committed to a comprehensive drug
development program which does not end with the receipt of the accelerated
approval letter. We believe that these
confirmatory trials to be an inherent part of the approval process. These
confirmatory trials are equally important as the initial trials for accelerated
approval. Confirmatory trials should be
carefully integrated into the development plan.
There
are reasons for the confirmatory trials to be considered as an integral part of
the total drug development plan.
Pragmatically the accelerated approval provides commercial drug to
patients and may interfere with patient accrual in the confirmatory trial. Hence consideration must be given to measures
that would ensure a timely completion of the confirmatory trial once
accelerated approval is awarded. These
may include additional sites or the expansion of the trial to geographic areas
where the drug may not yet be approved.
Integration
of the confirmatory trial early in the development plan allows further
questions to be formulated and answered.
These may include studying different doses or population pharmakinetic
investigations in the confirmatory trial.
As
stated, the division would like a thorough discussion of the confirmatory
trials early in the drug's development.
We envision discussions at the clinical trial milestones, at the
initiation and during the clinical trial.
These discussions should focus on timely accrual, problems with the
studies conduct and potential alternative trial designs and timely execution of
new trials if accrual or the expected outcome is not likely to be attained.
The
division encourages that these confirmatory trial be submitted to the FDA as
SPAs or Special Protocol Assessments, a provision that is a binding agreement
between the FDA and sponsor on an agreed-upon protocol. Both the FDA and the sponsor should have a
clear understanding of the regulatory term "due diligence" with
periodic review of timelines.
The
division has allowed accelerated approval examining patient populations in
refractory settings using single arm studies.
One reason for this approach is that even small response rates in a
highly refractory population may identify a drug with a unique mechanism of
action and bring novel agents to the clinic early. We have allowed the confirmatory trials to be
conducted in an earlier stage or less heavily treated population than the
initial accelerated approval.
Oncology
drug development as expedited by the earlier introduction of promising agents
to the first line and adjuvant settings.
Accelerated approval may limit accrual into confirmatory trials in the
approved indication. Allowing patients
to be entered in less refractory settings may obviate this accrual
problem. Nevertheless allowing the
demonstration of clinical benefit in a different population may leave the
question of clinical benefit in the accelerated approval indication unanswered.
Studying
drugs initially in a refractory setting presents problems. Response rates may be progressively smaller
in progressively more heavily treated patients.
Hence a promising agent may be missed.
Encouraging sponsors to study refractory patients can channel drug
development to progressively more heavily treated patients. This may lead to developing drugs in highly
selected groups of patients with natural histories and responses that may not
be easily extrapolated. In addition,
studying patients with extensive prior therapies may pose problems in
adequately characterizing toxicities because of chronic residual toxicities of
prior therapies or progressive symptoms.
Accelerated
approvals have been granted with the trial design using single arm trials in
refractory populations as stated previously.
These trials obviously allow more rapid trial completion and hence
expedite drugs to patients with life-threatening diseases. An alternative trial design uses a randomized
trial allowing accelerated approval on the basis of an interim analysis of surrogate
endpoints, for example, response rate or time to progression. These randomized trials also allow additional
endpoints other than response rates such as time to progression or time to
symptomatic progression. At the
completion of the trial, the clinical benefit endpoint of survival can be
evaluated. Randomized trials also allow
a greater understanding of comparative toxicity.
Randomized
trials also may optimize the evaluation of novel cytostatic agents by allowing
an assessment of slowing or retarding or preventing tumor progression. This may simply not be possible with single
arm trials. Randomized trials also allow
"add-on" trial designs where the novel agent is added to standard
therapy and then compared to standard therapy thus advancing standard and
routine therapy's practice in the community.
Obviously
randomized trials are more expensive than single arm trials and take more
time. Nevertheless there are also other
problems. Survival analysis can be
complicated and confounded by cross over and subsequent therapy.
Although
we have been discussing accelerated approval in Oncology, the other life
threatening condition where this regulatory provision has been used in the
accelerated approval of antiviral drugs in the treatment of AIDS. A slightly different strategy has been
employed. Usually two randomized trials
each approaching 1,000 patients are required.
The surrogate endpoint if viral load at 24 weeks which provides evidence
for accelerated approval. Full approval
is obtained with the same study by demonstrating the effect on the same
endpoint at 48 weeks. The same trial
provides support for accelerated approval and subsequently provides evidence
for full approval.
A
similar approach has already been discussed for Oncology drugs. Accelerated approval can be granted by an
improvement in response rates and time to progression in a randomized trial. Full approval may be based on a survival
advantage observed in continuing that exact same trial.
The
goal of this meeting is to provide a constructive dialogue with sponsors on
confirmatory trials aimed at demonstrating clinical benefit after initial
accelerated approval is granted. The
division wants this meeting and subsequent discussions to be proactive in
assessing study design issues, endpoints, accrual problems and timely
completion of studies. This is the first
of what the division plans to be recurring public meetings aimed at examining
mandatory clinical benefit trials in the accelerated approval framework.
The
mandatory confirmatory trials to demonstrate clinical benefits are equally
important as the initial trials demonstrating an effect on a surrogate endpoint
leading to that drugs approval. The
subsequent confirmatory trials provides the demonstration of ultimate clinical
benefit to the patient. Hence
confirmatory trials must be an inherent and integral part of a comprehensive
drug development plan and drug development strategy. Thank you.
CHAIR
PRZEPIORKA: Thank you. Are there questions for Dr. Pazdur or Dr. Dagher? Dr. Martino.
DR.
MARTINO: A basic question. During the same ten year period, many other
drugs have been up for approval and denied.
I need to understand a ratio here.
It looks like we approved 19 during this ten year period.
CHAIR
PRZEPIORKA: Dr. Pazdur.
DR.
DAGHER: First of all, just a
clarification, you mean by "denied" meaning applications that were
submitted for consideration for accelerated approval or in general.
DR.
MARTINO: No, that is exactly what I
mean.
DR.
PAZDUR: I don't have those data just off
the top of my head. I could get back to
you with them.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: Just before you leave, many of
those have actually come to this committee and there aren't very many. One of the points I wanted to make is you
might not know this from Mr. Walker's presentation. Accelerated approval is the way cytotoxic
drugs come to the marketplace. Almost
all of the drugs that are approved come this way.
The
sample sizes in the databases are modest by most reasonable standards. A couple hundred would be quite typical with
a ten percent response rate. You are
seeing 20 responses. That is the usual
way. Maybe that's not imaginative for
some people but that reflects a total change in the way cancer drugs are
developed. You can argue about whether
that's a good thing or bad thing. But it
represents a vast change.
CHAIR
PRZEPIORKA: Dr. George.
DR.
GEORGE: A question about the HIV model
and the use in Oncology. If I was
following this right at least in two cases this has already been used in
Oncology in the oxaliplatin and the anastrozole cases. Is that true?
Are there others?
DR.
PAZDUR: Those are the two primary
examples, yes.
DR.
TEMPLE: Can I say? But, Steve, oxaliplatin was unusual. You had to demonstrate the contribution of
each component so you had really no choice but to do a randomized control
trial.
DR.
PAZDUR: But nevertheless the concept of
having a randomized trial in place looking at an interim analysis of response
rate and time to progression because obviously one is allowed to do that
because of the randomized nature of the study and then letting that trial go on
to completion to give you full clinical benefit. That's the point I was trying to make. The hormonal therapy obviously was looking at
the endpoint where we wanted additional confirmation that the effect on the
endpoint was going to be maintained over a period of time.
DR.
DAGHER: And that concept is also applied
somewhat with the first line approval for CML for Gleevec that I outlined. So it doesn't fit that model exactly but it
does fit the model of allowing to study further looking at the same endpoint
with follow-up for more confirmatory evidence of that same endpoint.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: Models are nice when things
fit. It's a good point in your policy
that the confirmatory trials should be in place. But what happens when the confirmatory trials
have already been conducted and they are negative?
DR.
TEMPLE: The Committee obviously just saw
a case like that. Nobody can tell you
what the outcome of that is because it hasn't happened. Obviously in response to your question, if
your idea was that was where you were going to do the confirmatory trials, you
are in considerable difficulty and you have to figure out how you can do them
in the population that was in fact the accelerated approval population after
the drug is approved. The difficulties
of that are formidable. So nobody has a
quick answer to that question.
DR.
PAZDUR: You also have to analyze why the
trials failed. Just because a trial
fails does not mean that the drug does not work. There obviously could be methodological
problems. Those really need to be
discussed. Methodological problems could
be inadequate power of the study, inadequate numbers of patients in the randomized trials, problems
with stratification, a whole host of trials.
Nevertheless I think that is perhaps a cogent questions and needs to be
addressed in the discussions. We'd like
to hear your opinions on that as we have general discussions on this.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: What role does the unmet
medical need play in the accelerated approval process? Once the confirmatory trial is done and
perhaps in a population where unmet medical need is not an issue, how does that
play into that agency's thinking?
DR.
TEMPLE: The accelerated approval only
applies and can only be used for a serious or life threatening disease where
the new therapy promises something different. That could mean it's first therapy in the
class. It could mean it's effective in
people who didn't respond. It could be a
major safety advantage. Any one of those
things. That's the only circumstance in
which accelerated approval can be used.
The
second part of your question is once you've approved something under
accelerated approval what happens to other drugs. Is that what you are asking? I'm not sure if I understood the question.
DR.
BLAYNEY: It was inspired by Dr. Cheson's
remark about if the confirmatory trial is negative. Or Rick's remark on different study
populations if that unmet medical need is not applicable in the confirmatory
population.
DR.
TEMPLE: The accelerated approval rule
comes with a never used to-date accelerated withdrawal. Instead of the usual elaborate hearing
process, it would come before an advisory committee and that would be
expedited. It turns out that it is fair
to say that the circumstances in which things don't work out are always at
least somewhat ambiguous.
When
a drug has proved active in a setting where nothing else worked, you don't
lightly remove it because a trial failed to show overall survival effect. Many trials fail to show overall survival
effect. The details of what happens when
it fails are hard to say. You are going
to see some examples that will lead to a discussion of that. It's pretty obvious that you don't withdraw
an active drug lightly. You try to do
other studies. You think about why the
studies failed. These are many of the
things Rick talked about.
DR.
PAZDUR: One of the issues that you bring
up are twofold. The unmet medical need
really has been the foundation that has allowed us to take a look at the single
arm trials in doing these studies in refractory patients. It doesn't necessarily mean that you have to
do it in a refractory population.
The
other aspect of your question is if you have a drug that is approved for second
line or third line colon cancer and you get the confirmatory trial of clinical
benefit in the first line, what implication that has. We imply that clinical benefit has been made
and that is a full approval and extends basically to that indication. So another drug under our current
interpretations would have to go and examine if they wanted to examine an unmet
medical need to the fourth line colon cancer population.
We
are having some internal discussions now on this based on that exact subject of
whether we want to look at randomized study in that exact indication if
clinical benefit has not been met. Those
are on-going.
DR.
BLAYNEY: Is this unmet medical need
constract? It seems to me there's a lot
of moving around or permutations or difficulties with the sponsor trying to
find a niche that may or may not be appropriate and does not reflect what I do
every day.
DR.
PAZDUR: That is a very big problem
because what is my unmet medical need could not be your unmet medical
need. You could say the whole field of
Oncology is one big unmet medical need.
The issue here is the available therapy aspect does not necessarily mean
approved drugs but it's usually approved drugs.
If we're going to say that there is available therapy, we would like to
have confidence that it is at least a generally accepted regimen or treatment
even though it may not be approved., Something that would have some scrutiny
that it could come in for example as a supplemental NDA, that type of level of
proof.
Here
again one of the major problems that we have that I tried to allude to is the
fact that we have this game of drug X is in second line. Can we go to third line and then maybe we'll
go to fourth line? That can get into a
progressively more refractory population.
As people know that sub-selects out very unique populations of people
with unique natural histories. Their
responses and that data may not extrapolated to the general first line
population.
One
saving grace for this obviously is once you do introduce the confirmatory
trials to the earlier stage, then these drugs are then used earlier. What was once considered a second line
population for example in colon cancer Irinotocan treated patients that drug is
now used in the first line setting with
5-FU. So the second line and
third line keep on changing based on the introduction of drugs into earlier
settings in combinations.
CHAIR
PRZEPIORKA: Dr. Temple, you mentioned
earlier that when you would consider a withdrawal that it would come before the
Committee. Could you clarify please the
Committee's role in the withdrawal process?
DR.
TEMPLE: I'd have to read it again. Ordinarily if you want to withdraw a drug,
you go through a Notice of Opportunity for Hearing. There is a hearing before an administrative
law judge. In this case, the hearing
equivalent is before the advisory committee which then advises us. The final decision is still made by the
Commissioner but it's obviously a powerful role.
I
wanted to make one more observation because you may want to discuss this. One of the reasons one might think of doing
the confirmatory studies in an earlier phase is that the response rated is
modest say 10 percent there's a fairly good chance that you will not move
something like overall survival with a response rate that low. We actually take the fact that the drug in
different setting with a higher response rate can actually affect the clinical
endpoint as evidenced that if you like a proof of concept that this is a drug
that can have effects on the desired outcome even if you can quite figure out
how to do the study to show that when the response rate is so low. You might want to discuss that reasoning
because it's hard to prove but that is one of the reasons. From the beginning we've been satisfied with
studies in other settings as providing that evidence.
DR.
PAZDUR: And as I attempted to point out, in these heavily refractory patients
they've already received all of the standard therapy that we would accept. The likelihood of exploring and finding
unique mechanisms of action might be their novel agents. One would expect obviously the response rates
are usually lower in a more refractory population. As one moves them up to a first line setting,
then there would be a higher response rate and a more easy time identifying and
confirming clinical benefit.
CHAIR
PRZEPIORKA: Another question for you,
Dr. Pazdur. When sponsors give their
presentations at these meetings, they go into a very detailed, in-depth
literature review. But when the FDA
gives their presentations, it sticks to the data. Once the drugs are out there,
obviously there are some investigator initiated trials going on. At any point in time, do you ever take into
account negative trials in the literature or negative investigator initiated
trials for which you have data on other INDs when thinking about withdrawing a
drug?
DR.
PAZDUR: On the withdrawal of a drug, I
haven't been in that situation to withdraw a drug so I can't comment on
it. I don't know. Bob, do you have a comment?
DR.
TEMPLE: We would if the trials of the
company were negative and all the other trials were negative and it looks like
there is no activity anywhere. Surely
that would influence. We might try to
gain access to the detailed data because we like to do that. We would look at the entire database.
DR.
PAZDUR: And that's true in making any
regulatory decision. It's not confined
just to those trials. It has to look at
the totality of evidence in all trials and in anything that could support or
negate a result. Just for
clarifications, many times our
presentations are somewhat abbreviated from the sponsors just to avoid
duplication of material when we do present here. It may be a technical factor so that's why
please read the full Medical Officer's review because those reviews have very
comprehensive reviews of the literature on existing therapies.
CHAIR
PRZEPIORKA: Dr. Pelusi.
DR.
PELUSI: Over the few years that I've
been here my amazement has also been as the drug come to us looking at the lack of information in
terms of quality of life and in terms of symptom management. We see a fair number of patients leaving the
clinical trials due to either side effects or disease progression. But we don't have a lot of the information of
what does it mean for those people to really experience that drug. If we manage symptoms better, would they be
on it longer and would we see something different in terms of response? My question to you, Dr. Pazdur and your team,
is when you are setting up those confirmatory studies, is that mentioned in
terms of really looking at side effect management and quality of life studies.
DR.
PAZDUR: Yes, for the demonstration of
clinical benefit, that can mean several aspects. Although many people equate it only to
survival that simply is not true. We
have taken a look at disease related symptoms and have approved drugs on this
basis. We do ask the sponsors to
consider a time to symptomatic progression in many cases which we would
consider evidence of clinical benefit.
It is not simply a knee jerk reaction clinical benefit equals
survival.
These
areas of symptom benefit and quality of life are notoriously difficult. We've discussed this aspect in many ODAC
meetings. They include methodological
problems. They truly need a randomized
study. They have to be an integral part
of the trial and not just an add-on as to a quality of life because somebody
might like it. It really has to be an
integral part. Very difficult to do.
DR.
PELUSI: And I appreciate that. If I can just make one other comment about
that. Clinical trials are difficult
anyway but it really behooves us to really look at quality of life data. The other thing that concerns me in terms of
quality of life is many times the only quality of life data that we see is only those who complete the trial. It becomes important for us to look out of
the box to say we still have patients and families that went through that
experience as well.
When
we are looking at some of these confirmatory trials, whether the patient
completes that we may need to put in a family quality of life. That tells us as that drug becomes available
or not what is the impact on patients and families. Just for discussion.
DR.
PAZDUR: Very interesting idea because
obviously cancer does not only affect the patient but the patient's
family. As you can see by the public
comments that we frequently have, it is not only the patient. It is the entirety of the family that
experiences the disease.
CHAIR
PRZEPIORKA: Ms. Mayer.
MS.
MAYER: I still have a question about the
issue of unmet medical need.
Specifically in the case of adjuvant Anastrozole, it's not clear to me
how that particular indication meets this criteria except insofar as there may
given the interim data analysis on the ATAC trial be a slight improved
benefit. Does this mean then that the
sponsor involved in any randomized trial where there may be a slight
improvement can come to FDA and apply for accelerated approval for that
indication for their drugs?
DR.
PAZDUR: First of all, that was not an
unmet medical need because obviously in the adjuvant setting there is an
approved drug for that. The issue is one
where we have a situation where we were uncomfortable about the sustainability
of the effect and wanting more follow-up data looking at that. If one does demonstrate an improvement over
existing therapy in a life threatening disease then yes it would be appropriate
on the basis of a surrogate endpoint to look at accelerated approval or
consider it.
But
the unmet medical need issue, I really don't look at that as the inherent
reason why that drug was given accelerated approval. It was primarily because of the plausibility of the endpoint
which needs to further substantiated through follow-up. Do you have a different opinion?
DR.
TEMPLE: You couldn't do it unless there
was an unmet medical need because that's what the rule says. So we do interpret an advantage over existing
therapy as meeting an unmet medical need.
I guess you could consider that's not exactly what the word says but we
do.
Can
I make a comment about symptoms? We are
very interested in people looking at symptoms and quality of life. A lot of money has been expended trying to do
it with on the whole not such great results.
I just want to make a pitch for something that we never see but comes up
all the time. If people could
demonstrate an improvement in symptomatic time to progression, we would not
consider that a surrogate endpoint. That would be considered a clinically
meaningful endpoint. I have to tell you
that you hardly ever see trials that even try to assess that. I just want to make a pitch that someone
might want to do that.
CHAIR
PRZEPIORKA: Dr. Redman.
DR.
REDMAN: I have a question about the
requirement for a confirmatory trial.
Let me just say I'm a firm believer in Phase III trials. But in situations where the regulatory
defined standard of care may not be the standard of care in the community or
where there is no standard of care is a well-designed large Phase II
registration trial that could be acceptable as adequate endpoints as a confirmatory
trial.
DR.
PAZDUR: A large Phase II looking at what
type of endpoint though? You would have
to look at a clinical benefit endpoint ultimately.
DR.
REDMAN: A clinical benefit endpoint
being one that got it accelerated approval response rate, increase in symptoms.
DR.
PAZDUR: Symptoms obviously but here
again and we've discussed this with other applications demonstrating symptom
benefit in a single arm study may be methodologically difficult. In some areas, we have looked at response
rates to be clinical benefit. Those are
leukemia for example because a complete response would correlate with a
reduction in transfusions linked already to an improvement in survival in small
cell lung cancer because of its very rapidly progressive nature. We've had a drug approved on the basis of
looking at response rate with some symptom benefit.
DR.
REDMAN: In a Phase II setting.
DR.
PAZDUR: That was I believe in a Phase
III setting. That was a randomized
trial. But here again if we are
convinced that there is a strong linkage there, then that could be a
consideration.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: Just a couple of issues to seek
clarification. Is it appropriate to
assume that the strength of evidence that we would expect for establishing
benefit when that evidence is obtained from post marketing studies after an
accelerated approval would be comparable to what you would have required if you
were looking at a full accelerated approval?
That's question one.
Is
it also true that we should assume that there is the same sense of
urgency? We have a sense of urgency in
drug development prior to an accelerated approval. Is it fair to assume we would have that same
sense of urgency for how the timing of this assessment would need to be done
after an accelerated approval as we're conducting those trials upon which we
would ultimately hope to establish whether there is clinical benefit?
My
sense is that the regulations assume there would be such sense of urgency,
issues such it's assumed that usually these trials would be underway. Rick, these are your comments which are very
well taken about how you can achieve this timeliness by having, for example,
the randomized trial underway and maybe doing a interim analysis on a surrogate
endpoint which also reflects the sense of urgency and the document indicating
that if the applicant fails to perform the required post marketing study with
due diligence that there would be this accelerated withdrawal.
One
more aspect to my question is that if this study that you planned is negative
or at least is not conclusively positive what is the agency's philosophy on
this. In the final document that you
provided to us there's a sentence that says "A study that fails to show
clinical effectiveness does not prove a drug has no clinical effect but it is a
study that will lead to a withdrawal procedure because it has failed to show
that the surrogate endpoint on which the approval was based is correlated with
a favorable clinical outcome."
In
wrapping all this up, what is your philosophy?
Is it five years, seven years, ten years for a process of validating
clinical benefit something that fits
within the spirit of what was intended with accelerated approval? At least some of us think back to the
beginning of time where this process was initiated in settings such as HIV-AIDS
where we had NIH sponsor trials that were nearing their completion when
surrogate endpoints were used to get the accelerated approval where it was
almost eminent that a full approval assessment could be made. It's philosophically unclear how much
flexibility we are allowing for the timeframe once the accelerated approval has
occurred and what we are doing to ensure that there is this sense of urgency to
get a timely answer.
DR.
PAZDUR: You've hit the nail on the
head. That's why we are having this
meeting. I want to instill a sense of
urgency. It's very important and that's
why I gave the presentation that I did that there has to be earlier discussions
here with the agency. We're taking this
as a serious aspect. This is equally as
important as the response rates.
Remember
with any program there is an evolution and a taking a look at history of the
program. That's why we are doing it at
this time. What are the lessons that we
can learn from these applications to take forward and to improve the
program. The success or failure of the
program is simply not whether Phase IV commitments have been met. There are many reasons why these commitments
may have not been met and you'll be hearing them.
Nevertheless
my reason for personally being the initiative behind this meeting is that I
wanted the light of day on some of these applications and I want basically this
to be a recurring meeting. For the
sponsors that are not here because their applications are too early, we'll be
seeing them again next year or in an 18-month period of time. This is not the final meeting on this.
Secondly,
the reason why I wanted this trial initiated earlier, the truly successful
trials that we saw that completed their trials in a very expedited fashion were
those trials that were on when we approved the drugs. We really want to emphasize that to the
sponsor. I don't want to get dogmatic
here where we say I will never approve a drug unless the trial is on-going and
has completed accrual because that may be counter productive in denying
patients access to the drug.
Nevertheless
I would like that to be the exception than the rule. Over the past 18 months, the drugs we have
not seen we have seen a commitment by most of the sponsors to have a greater
commitment in fulfilling and initiating these trials in a more timely
fashion. There is nothing more important
than the sunlight of the day and the sunlight of public opinion to get people
motivated to fulfill the commitments.
That's why we are having this meeting.
To
answer the other part of your question as far as level of proof, we have to be
convinced that this drug works. It
should be the same level of proof that we have for a full or conventional
approval of the drug. There is no different evidentiary level of proof
for accelerated approval of the drug.
DR.
FLEMING: So just to summarize what I'm
hearing the strength of evidence should be comparable. The second point is if I'm interpreting this
correctly there needs to be due diligence.
There needs to be a timely ascertainment of that level of strength of
evidence. In the absence of that, then a
withdrawal should in fact occur in the spirit of these regulations.
DR.
PAZDUR: Yes.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: I would like to unfortunately go
back to what we discussed a little bit earlier about unmet needs. Please take this in the spirit of someone who
takes care of diseases that actually respond to chemotherapy and other forms of
biological therapies.
The
situation that we may have come into not too long ago and may come into again
in the future is when you have the agency presented with two first-of-class
compounds. At some point in time have
agreed on a particular patient population.
The trials go on with these two compounds. One of them gets approved and the other one
comes up six or 12 months later. What
happens then? There is no longer an
unmet medical need. Both are let's say
60 percent drugs unlike what you see in lung cancer. They are both highly effective agents. How do you deal with that situation?
DR.
TEMPLE: And your supposition is they are
both accelerated type approvals. They
don't have a clinical outcome yet. Is
that what you are asking?
DR.
CHESON: Yes.
DR.
TEMPLE: The answer to that will be
coming fairly soon. We're working on
that problem and agree that it is a problem.
There is uniform agreement that the intent was not to kill off
appropriately started drugs. We're
looking at current regulations and guidance and I can't say more.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: Dr. Temple made the comment
earlier that it's very difficult to withdraw a drug that's received accelerated
approval on the basis of a surrogate endpoint.
If the confirmatory trials are negative because they are very difficult
diseases, there may be no obvious alternative to that particular
treatment. It would mean to me that the
surrogate endpoint should have been very strong at the beginning that led to
accelerated approval.
As
part of our discussion, it might help me if I had a better idea of acceptable
surrogate endpoints or knowing that you can't write this into an iron. It also seems that it may be as we move
forward in the future that we're looking at small groups of patients who
respond to individual treatments. We see
that all the time. So there is some
reason why they respond which hasn't been defined.
Maybe
we could discuss this. I wonder if
you've thought about when the drug comes for accelerated approval and we only
see a 10 or 11 percent response rate if we require the sponsors to have a
really plausible biological reason why that may occur or we include that in the
confirmatory trial that they are required to demonstrate why those 10 people
responded or did well and others didn't, understanding the challenges of that
type of thing.
DR.
PAZDUR: That's a problem. The way the regulations are written is the
surrogate endpoint should reasonably likely to produce a clinical benefit. It doesn't say that has to be a definite
surrogate for clinical benefit. It
doesn't say that has to be a proven benefit.
Reasonably likely in the eyes of the beholder. That's why we have brought many of these
accelerated approvals especially when they tend to be on a more meager level of
response rates. It's a decision that is
a clinical decision ultimately that has to be made on the stage of the disease,
the refractoriness of the population.
This is a difficult issue. It was
written in such a way and Bob could comment on this far more appropriately than
I can since he was involved with writing the regulation that there was this
flexibility in clinical judgment to be entertained.
DR.
TEMPLE: This was written at a time when
certainly the Oncology community pretty much to a person believed that in
refractory disease if you had something that successfully shrank a fraction of
the tumors you had something that was promising. As endpoints go, shrinking tumors is not
usually crazy. That is the tumor that's
doing something and it isn't farfetched to think that's a reasonable endpoint.
One
current development and we'll probably have to come back to on these matters is
that as Rick said before shrinking tumors may not be the thing that a given
drug does best. It may delay progression
or something like that. It's very hard
to establish in a single arm trial.
One
of the things we've been certainly talking to people about is to make these
early studies that are in fact randomized with a control group from the
earliest beginning. That gives you in
some sense two shots at finding something useful which also raises the question
which we have brought to this Committee many times about whether time to
progression is an endpoint that needs to be considered more seriously.
One
of everybody's biggest problems is that it's extremely hard to keep people from
crossing over. Whatever you think the
effect of crossing over is it has to direct the study toward the null. It has to.
Finding overall survival in these settings is increasingly
difficult. We will come back to that
again. The Committee has always said do
survival but perhaps some modeling on the effects of what cross over does. We need to consider whether that's a
surrogate endpoint of a somewhat more persuasive kind.
CHAIR
PRZEPIORKA: I don't want to stifle the
conversation here but I just want to point out that the more discussion we have
the less lunch we get. On the other
hand, this is one incredibly detailed part of the law that we actually need a
lot of information on. So I do want to
go on with the questions. Dr. Martino.
DR.
MARTINO: I need to understand a very
basic issue here. Once accelerated
approval has been given, you then allow the sponsor the opportunity to prove to
you that there is more value to their drug
and therefore to get full approval.
Is there a timespan during which they have to do that? It strikes me that this is left as a somewhat
extremely variable experience for them.
I'm not sure that I'm understanding that in fact there are consequences
to their not actually fulfilling their commitments.
In
other words, how often does the Committee, the FDA, the group, actually then go
back and say we're taking that drug off because you've not met your
commitments? What degree of threat in
reality not in concept actually exists?
DR.
PAZDUR: Let me answer that
question. First of all, the action to
demonstrate clinical benefit as I was pointing out we really don't want that to
occur after the approval. That should be
an integral part of the development process and be discussed with the agency
while the drug is being developed.
We
have seen this in the past, Silvana, where a drug basically comes to the
Committee and should the drug receive accelerated approval or not. Yes.
The FDA and the Committee or the FDA and the sponsor after the drug
receives or during the labeling of the drug will discuss the clinical benefit
trial. That is probably a situation that
is suboptimal.
As
I pointed and my purpose in giving the talk was that we are revisiting this
program and this is the whole essence of this meeting as far as trying to bring
this to light that these trials need to be an inherent, integral part of the
program, discussed while the Phase II trial is on-going and before the end of
Phase II meetings.
The
preamble to the regulations state that these trials would be expected to be
near complete enrollment. I have not
been dogmatic because here again I don't want to deny therapies to people that
may benefit by just waiting for these trials to be initiated. We have allowed some degree of flexibility.
How
much time does somebody have? It's
defined relatively loosely again in the regulations and probably appropriately
so. It states with due diligence. What does that mean? We're reviewing that. As I mentioned in my presentation, I want to
have an on-going discussion on a periodic basis with sponsors regarding this
definition and their interpretation of due diligence and my interpretation of
due diligence here which may be different.
There
are some diseases obviously that are going to take a long time to do. They are rare diseases. You will see some examples of this. We would not accept years to do a lung cancer
trial. But for a very uncommon disease,
there has to be some flexibility here.
DR.
MARTINO: What about the consequence?
DR.
PAZDUR: Consequences as Bob pointed out
and as Ramzi did also, there is in the regulations a withdrawal procedure that
can be initiated by the Center director.
It has to come back here ultimately.
The indication, not the drug, can be taken from the sponsor after a well
defined process here. This has not been
done in Oncology to-date and I'm not aware of any of the AIDS drugs being
removed.
Obviously
the agency has removed drugs for toxic effects, unexpected toxicities,
etc. Those are well known and well
documented. I am unaware of one being
removed because of lack of efficacy. I
don't know if Bob wants to comment on that.
DR.
TEMPLE: Many years ago a drug called
Betahistine was taken off. It's
comparatively unusual because we usually have a pretty good idea they work. The thread is there. The actuality would come down to the specific
cases. We're clearly prepared to do that
but you can imagine that there will be arguments about how definitive the
negative study is. The absence of
evidence isn't evidence of absence and all that stuff. So it would be a discussion. That's why we bring it to outside minds.
DR.
MARTINO: So it strikes me that the
threat is fairly minor in practicality.
Is that what I'm hearing?
DR.
TEMPLE: No, I would say if somebody
didn't flat out do them and there was no good excuse we would move on it. We really haven't encountered that.
DR.
PAZDUR: "Past history need not
predict future trends." E.F.
Hutton.
CHAIR
PRZEPIORKA: Mr. Ohye.
MR.
OHYE: I think my question has been
answered but I'd like to ask that you are not moving toward the requirement
that patient accrual has to be on-going at the time of accelerated approval,
are you? In other words, is that going
to be a condition precedent?
DR.
PAZDUR: No.
MR.
OHYE: Because everyone knows, there are
enumerable operational issues to get to that stage. As long as the sponsor is acting in due
diligence to get the trial moving.
DR.
PAZDUR: George, I made explicit comments
that I thought that I would not want to do that because that would be
ultimately unfair to many patients who really need the drug to arbitrarily just
say we need to have this trial on-going.
So we have demonstrated the flexibility even though in the preamble it
clearly states that it was intention that these should be on-going. I wouldn't mind. I would love it obviously.
But
I would like and I don't think this is being overly regulatory to have really
thorough discussions with the sponsor before that NDA is submitted about what
is their confirmatory trial, what are your back-ups for this, what trials are
being done. Please label your trials as
these confirmatory trials so we don't get into a situation as we did a couple
of months ago where there were Phase III studies being done and the sponsor
saying these really weren't confirmatory trials. They have to be labeled and discussed.
Sometimes
there's implicit understanding with the agency we thought. But that doesn't necessarily mean that this
is what is in existence. We really want
to have a thorough understanding before we even accept the NDA. I keep using these words but this should be
an integral part of a drug development strategy. It is not an afterthought. The drug approval does not stop with the
approval letter.
MR.
OHYE: Thank you.
CHAIR
PRZEPIORKA: Dr. Reaman.
DR.
REAMAN: Rick, you may have addressed it
with the issue of back-up plans. But
just for clarification in the setting of a negative confirmatory trial, if
there are methodological issues which could in fact be a possible explanation
for why the trial failed, what is the policy or procedure as relates to
accelerated approval for permitting, encouraging an amendment or restructuring
of that trial or the development of another confirmatory trial?
DR.
PAZDUR: First of all, we would have to
have demonstration of clinical benefit.
Whether that occurs through reopening a trial versus a new trial, that
gets really down to the science of the trial basically and the integrity of the
trial if one would reopen it. But there
is no wiggle room here. It's not that we
would take a trial and say we think you've demonstrated clinical benefit even
though you have not met your endpoint.
That goes back to Tom's question.
It's the same evidentiary level of proof as we would want for a full
approval of a new drug. If there is a
problem then that becomes a negotiating point of what is good science as far as
the reopening of a trial or looking at another indication.
It's
important and one of the points that I want to get across is this is somewhat
of a different situation for sponsors than basically gambling on whether a drug
is going to be approved by the FDA. They
already have a drug that is out there being marketed. Therefore I feel somewhat passionate here
that they need to really put a full force in getting these approved even if
it's multiple trials. The drug is out
there. It is a drug. It isn't a hypothetical drug.
So
they need to have one trial or two trials or three trials. I don't care how many there are but there
needs to be an adequate commitment on the part of the pharmaceutical sponsor
and their management that this is a real commitment and that it should be
handled with the same vim and vigor as they go after obtaining an approval of a
new NDA to market the drug.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: It's worth remembering the
premise. The accelerated approval rule
specifically accepted a lower than usual standard. Usually you are supposed to show that there
is clinical benefit or have a surrogate that everybody believes is fully
acceptable. This said we can use
surrogates that are not of that quality that are more iffy than that for a
particular reasons to serve an unmet medical need. Inherent in that was the idea that you would
get the right answer. It's easy to
forget that probably when the drug's out there.
But as Rick says he feels very passionate that you are supposed to think
of that from the beginning. It's the
whole deal and not just this little piece of it.
CHAIR
PRZEPIORKA: Any other questions for the
FDA? Thank you. Now we are going to move on to the next item
on the agenda which is actually we all know each other here and are very
comfortable talking to each other. But
we need to introduce ourselves to the speakers.
I want to go around the table and have everybody speak into the
microphones so the transcriptionist can hear us and introduce yourself. Mr. Ohye.
MR.
OHYE: George Ohye, Industry Rep. In the interest of full disclosure on
conflict of interest, I also own shares in many of the competitors of Johnson
& Johnson, some of whom will also present today.
DR.
FLEMING: Thomas Fleming, University of
Washington, Seattle.
MS.
MAYER: Musa Mayer, Patient Rep, New York
City.
DR.
PELUSI: Jody Pelusi, Oncology Nurse
Practitioner in Arizona and I sit as the Consumer Rep.
DR.
REDMAN: Bruce Redman, University of
Michigan Comprehensive Cancer Center.
DR.
TAYLOR: Sarah Taylor, University of
Kansas Medical Center.
DR.
REAMAN: Gregory Reaman, Pediatric
Oncologist, George Washington University Children's Hospital in the Children's
Oncology Group.
DR.
CHESON: Bruce Cheson, Georgetown
University, Lombardi Cancer Center.
DR.
CARPENTER: John Carpenter, medical
oncologist, University of Alabama, Birmingham.
DR.
BRAWLEY: Otis Brawley, medical
oncologist and epidemiologist, Emory University, Atlanta.
CHAIR
PRZEPIORKA: Donna Przepiorka,
Hematology, University of Tennessee Cancer Institute.
SECRETARY
CLIFFORD: Johanna Clifford, FDA,
Advising and Consulting Staff, Executive Secretary to this meeting.
DR.
BLAYNEY: Doug Blayney, medical
oncologist, Wilshire Oncology Medical Group in Pasadena, California.
DR.
GEORGE: Stephen George, biostatistics,
Duke University.
DR.
LIPPMAN: Scott Lippman, medical
oncologist, M.D. Anderson Cancer Center.
DR.
MARTINO: Silvana Martino, medical
oncologist from the John Wayne Cancer Institute in Santa Monica, California.
DR.
KELSEN: David Kelsen, medical
oncologist, Sloan-Kettering, New York.
DR.
DAGHER: Ramzi Dagher, Medical Officer,
Division of Oncology Drug Products, FDA.
DR.
RYAN: Qin Ryan, Medical Officer, CDER,
FDA.
DR.
PAZDUR: Richard Pazdur, FDA.
DR.
TEMPLE: Bob Temple, FDA.
CHAIR
PRZEPIORKA: Our first presentation is
listed as Dr. Steven Hamburger from Johnson & Johnson Pharmaceutical, NDA
50-718 of DOXIL indicated for the treatment of Kaposi's sarcoma in AIDS patient
with disease that has progressed on prior combination therapy or who are
intolerant to such therapy. Dr.
Hamburger.
DR.
HAMBURGER: Thank you and good
morning. My name is Steve Hamburger and
I'm the Global Regulatory Strategic Leader for Oncology at Johnson &
Johnson Pharmaceutical Research and Development. My goal is to provide you with some
background information regarding the actions taken to fulfill Phase IV
commitments for DOXIL in the treatment for patients with AIDS related Kaposi's
sarcoma.
We
hope that this information will facilitate your discussions to provide guidance
on the accelerated approval process and the Phase IV commitment trials that
will allow conversion from accelerated to full approval. I will discuss some of the challenges we have
encountered in conducting Phase IV commitment trials in patients with this
disease. Some of these challenges may be
applicable to other diseases and some may unique to Kaposi's sarcoma (KS).
With
me today to answer any of your product specific questions are my colleagues
Drs. George, Mohanty, Teitelbaum, Tonda, and Zukiwski. In addition joining us for this session is
our consultant, Dr. Susan Krown, from Memorial Sloan-Kettering Cancer Center
who is an expert in the treatment of patients with AIDS-KS.
DOXIL
is indicated for the treatment of AIDS-KS in patients with disease that has
progressed on prior combination chemotherapy or in patients who are intolerant
to such therapy. The design of the
original Phase IV commitment trial was agreed upon with FDA before the NDA was
approved. The design of this trial
included input from the review division as well as ODAC members. We conducted this trial with due diligence
and provided the results in a supplemental NDA soon after the data was
analyzed.
Unfortunately
the regulatory action was not conversion to full approval. I will discuss the reasons for this as part
of this presentation. We are however
committed to work with the FDA and others to design an appropriate clinical
trial that will demonstrate the benefits of DOXIL in this patient
population. Discussions are on-going
with FDA and others regarding this trial design.
Since
the original approval of DOXIL in this patient population and during the
enrollment of the Phase IV commitment trial, the incidence of AIDS related KS
has dramatically declined. While this is
great news for patients infected with HIV, it is even more of a challenge to
enroll patients in a clinical trial.
This line represents the incidence of this disease between 1973 and 1999
and identifies the sharp decline in incidence since the mid-1990s.
The
introduction of highly active anti-retroviral therapy (HAART) during this time
is most likely the predominant cause for the rapid decline in incidence. Despite this decline, patients with AIDS
related KS continue to be seen and have severe enough disease to require
immediate systemic chemotherapy. Such
patients are a heterogenous group with respect to the status of their HIV
infection.
Although
some patients with advanced KS have well controlled HIV infection as evidenced
by an undetectable HIV viral load and a relatively high CD4 count. More typically the patients who present with
advanced symptomatic KS either fail to respond to adequately to antiviral
therapy or intolerance of such therapy or have other barriers to compliance
with therapy.
Another
challenge in conducting a trial to document the clinical benefit of DOXIL is
the fact that DOXIL is by far the most frequently prescribed chemotherapeutic
agent used by U.S. physicians to treat AIDS related KS. It has been estimated that 65 percent of
patient AIDS-KS treated with chemotherapy in the United States received DOXIL
either alone or as a part of combination chemotherapy. Whereas the next frequency prescribed,
Paclitaxel, was prescribed in less than 20 percent of patients. The preferential prescribing of DOXIL and its
commercial availability make it difficult to conduct an adequate and well
controlled trial.
In
September 1994, Sequus submitted the DOXIL NDA that contain safety and efficacy
information obtained predominantly from four clinical trials. Efficacy information was available for 383
patients while safety data was available for 753 patients. In this submission and a supplement provided
six weeks later, the FDA Medical Review focused on 77 patients retrospectively
identified as having disease progress and prior systemic combination
chemotherapy or being intolerant to such therapy. These patients were all enrolled in one study
designated as Study 30-12.
On
February 14, 1995, the ODAC recommended that DOXIL be approved under the
accelerated approval mechanism since the results of Study 30-12 represented
substantial evidence of efficacy in a treatment of refractory AIDS related KS.
Following
the NDA submission, there were on-going discussions regarding the design of the
Phase IV commitment trial. In June 1995
during the NDA review, the sponsor and FDA agreed to the design of this Phase
IV commitment trial. This was a double
blind randomized evaluation of the clinical benefits of DOXIL in patients with
AIDS related Kaposi's sarcoma randomized in a three to one manner to be treated
with either DOXIL or DaunoXome. The
start of this trial was dependent upon the commercial availability of
DaunoXome.
In
November 1995, DOXIL received accelerated approval for the treatment of
patients with AIDS related KS. The Phase
IV commitment trial designated as Study 30-38 was a double blind randomized
trial. We contacted 50 U.S.
investigational sites. Twenty-eight
showed interest in performing this trial but only seven sites participated in
this trial.
The
first patient was enrolled in September 1996.
It was approximately four months after the commercial availability of
DaunoXome. Patients enrolled in this
trial had AIDS related KS and could be either previously treated for this
disease or chemo-naive.
As
agreed with FDA, the primary endpoint was documentation of clinical
benefit. The trial was not designed to
test differences between DOXIL and DaunoXome.
The FDA agreed that demonstrating superiority was not needed for the
Phase IV commitment.
To
be eligible for this trial, patients had to have AIDS related KS of a severity
requiring systemic chemotherapy and one or more of the following systems. In addition they had to have five or more
measurable mucocutaneous lesions.
Efficacy measures was done by
clinical benefit as well as tumor response
utilizing the ACTG criteria.
Investigators assessed tumor response and photographs of patients were
also evaluated by an independent review blinded to patient treatment. The relationship between clinical benefit and
tumor response was also analyzed.
Clinical
benefit was defined as improvement in one of the five symptom categories
lasting at least four weeks in the absence of tumor progression or sever
drug-induced toxicity. Patients assessed
the five symptom categories using a questionnaire and rated the degree of
symptom interference with daily activities on a four point scale.
In
the left-hand column of this slide are the five symptom categories that we
assessed. On the right are specific
symptoms scored by the patients on the four point scale. To be eligible for enrollment in Study 30-38, patients had to have at least
one of these symptoms. These symptoms
may be debilitating, significantly altered normal activities of patients and
justified the immediate use of cytotoxic chemotherapy. You should keep in mind that in some patients
with less advanced KS may not have any of these symptoms and would not have
been considered candidates for chemotherapy in general or this study in
particular.
The
efficacy of DOXIL and DaunoXome are measured by clinical benefit and tumor
response as demonstrated in this study.
Please recall that this study was not designed to show differences with
treatment arms. The median time to
objective tumor response was approximately 30 days for each drug.
The
percentage of clinical benefit by each symptom category for each drug is
provided in this slide which shows that both drugs provided clinical in each
symptom category. This brief
presentation of some of the efficacy data from the Phase IV commitment trial
30-38 was provided to you so that you can understand the basis for ALZA's
submission of supplemental NDA (sNDA) in October 2001.
However
in July 2002 the regulatory conclusion was that changes in anti-retroviral
therapy confounded the FDA's efficacy assessment from Study 30-38. At the time of the original discussions with
the FDA to design the Phase IV commitment trial, standard anti-retroviral
therapy for patients with HIV infection consisted of single or dual nucleoside
reverse transcriptase inhibitors.
During
the conduct of Study 30-38, new anti-viral agents especially protease
inhibitors were found to be effective to treat HIV infections. Thus new combinations collectively known as
HAART were incorporated as standard treatments for many patients with HIV. Therefore many patients had changes made in
the drugs used to treat their HIV infection shortly before or during their
participation in Study 30-38. The
protocol which was written before the introduction of HAART provided no
guidance regarding HAART therapy.
We
have conducted an extensive review of the literature on this subject. While there is no doubt that KS regresses in
some patients treated with HAART, precise response rates are difficult to
estimate. Dr. Krown is here and can
address any of your specific questions regarding HAART or AIDS related KS.
In
the fourth quarter of last year, we convened an advisory board of U.S. AIDS-KS
experts. This was necessary as HAART
therapy was an important variable that FDA required be stabilized for accurate
assessment of the efficacy and safety of any systemic chemotherapy including
DOXIL to treat patients with AIDS related KS.
We
submitted a Phase IV commitment trial protocol outline in November. There are on-going communications with FDA
regarding a new protocol and development plan to confirm the clinical benefit
of DOXIL in patients with AIDS related KS.
In a February 3, 2003 meeting, we discussed potential clinical study
designs with the FDA. As yet, however,
we have not come to an agreement on the design of a trial that can be conducted
in a timely manner.
In
summary, although we continue in our commitment to provide convincing evidence
for the clinical benefit of DOXIL in patients with AIDS related KS in 2003
there are significant challenges for protocol design and clinical trial
implementation. The incidence of KS in
2002 has been estimated as about 1500 patients.
Diseases of an incidence of this degree have been termed "ultra
orphan diseases" and present special challenges for the design of clinical
trials.
In
practice when chemotherapy is indicated, DOXIL has been the predominant choice
for first line systemic chemotherapy of AIDS.
This limits enrollment of potentially eligible patients into a clinical
trial and as they have a choice to receive commercial drugs at the in-site of
their primary HIV care rather than seeking treatment at a clinical trial site.
Many
patients who present with AIDS and KS who require aggressive intervention are
treated concomitantly with HAART and chemotherapy. The effect of HAART alone on AIDS-KS
regression is not well documented. As we
have described earlier, the literature contains some information but not from
adequate or well-controlled trials. In
some cases, the efficacy attributable to HAART has occurred during the
administration of concomitant systemic chemotherapy.
Even
when KS regression occurs after the introduction of HAART alone, the available
data indicate that the time to response is months after the introduction of
HAART and not the rapid reduction observed with chemotherapies like DOXIL. Finally the on-going introduction of new
anti-retroviral agents will further confound interpretation of future study
results.
Not
all patients with AIDS-KS require systemic chemotherapy. It is not acceptable to delay cytotoxic
chemotherapy when medically indicated and such a trial design may not be
executable. Thus based upon this
information, it's difficult to conduct a placebo-controlled or active
comparator-controlled trial in this relatively small patient population. For example, there was insufficient accrual
in the joint ECOG, SWOG and AIDS Malignancy Consortium study comparing two
approved drugs, Taxol and DOXIL in patients with AIDS related KS which recently
led to premature study termination.
In
conclusion, we are committed to design and implement with FDA agreement a new
Phase IV trial as quickly as possible to convert this accelerated approval to
full approval but acknowledge that there are substantial barriers to
overcome. Thank you.
CHAIR
PRZEPIORKA: Thank you, Dr.
Hamburger. Dr. Pazdur, does the FDA have
any comments or questions that you want to specifically address regarding this
product?
DR.
DAGHER: I have a general comment. You mentioned in the summary that we've had
on-going discussions and that different potential designs are being
contemplated. Could you just in general
comment on what kinds of trials you've been contemplating? I know that you may not have all the
specifics but just in general the kind of trials that are being contemplated.
DR.
HAMBURGER: We originally considered a
single arm study comparison to baseline.
That was not acceptable. There
have been some other comments by the FDA but I would like Dr. Zukiwski to maybe
answer those specifically.
DR.
ZUKIWSKI: We've entertained a number of
different trial designs with our FDA colleagues. I think those discussions are on-going and
including things such as delaying initial cytotoxic treatment and seeing where
the response will come in terms of time.
At the present time, it is a very difficult trial to design. We're working very closely with our FDA
colleagues to come to a reasonable trial design which will demonstrate clear
cut clinical benefit in this patient populations.
CHAIR
PRZEPIORKA: Are there any questions from
the Committee to the sponsor? Dr.
Redman.
DR.
REDMAN: In your slide presentation, I
have two questions from it. You
presented on use in the community of DOXIL versus Taxol. I was wondering how is that data accumulated,
how accumulated it and has it been published.
DR.
HAMBURGER: That data comes from a public
database called Tandem. While the sample
size is small, it's the only data that we can find regarding the utilization of
any systemic chemotherapies to treat patients with KS.
DR.
REDMAN: I'm not familiar with the
database. Who does it?
DR.
ZUKIWSKI: The data is obtained from a
company called Tandem. What they do is
perform market research. They look at
trends and treatment. They take a sample
of various treating physicians that have AIDS related KS in their
practice. Mind you, it's a limited
sample because you can't blanketly canvass all the physicians in the United
States so it is basically the trends in chemotherapy treatment for patients
with AIDS related KS.
DR.
REDMAN: Okay. The second question I had was related to your
reference to an expert panel that was convened in the fall of 2002. What were the results of that regarding their
thoughts and design of a trial and also who convened that panel?
DR.
ZUKIWSKI: The panel was convened by
Johnson & Johnson and Ortho Biotech.
We had approximately 12 members, all who are recognized experts in the
area. We sought advice from them and
there were the seven or eight advisory board members to get their input in
terms of the non-approval letter, the recommendations that the FDA had to try
to come up with the most reasonable trial design which would be executable and
demonstrate clinical benefit in this patient population.
DR.
REDMAN: What were the results?
DR.
ZUKIWSKI: We went through numerous
different gyrations trying to come to a conclusion of what the best trial
design would be. The FDA has requested
that we have patients enter into a trial that are stable on their HAART so they
have stable anti-viral load, a stable CD4 count, etc. Looking at that patient population, we
proposed one type of trial. We didn't
believe we could execute a randomized trial because patients would not accept
another treatment arm as evidenced with the previous ECOG-ACTG trial.
We
recommended a straight forward simple Phase II trial using the patients as
their own baseline with clinical benefit using the AIDS Malignancy Consortium
questionnaire and using the patients themselves as their own baseline.
DR.
REDMAN: That was the recommendation of
the panel.
DR.
ZUKIWSKI: That's what we came up with
after numerous different discussions.
There was consideration given to those patients who present de novo with
the neglected AIDS, those individuals who were intolerant to HAART, who will
not take it for various social reasons, who present with large volume disease,
etc. So that numerous considerations
were given to potential trial designs.
CHAIR
PRZEPIORKA: Dr. Hamburger, this is going
to be a rather interactive session so if you wish to just keep your place at
the podium, you may be more comfortable doing that. Dr. Fleming.
DR.
FLEMING: I'd just like to have
clarified. In your original letter on
June 28, 1995, in your original Phase IV commitment, am I correct that it was
in fact the 30-38 trial that was to serve as the basis of obtaining evidence to
establish benefit? If in fact that's the
case, my understanding was you weren't limiting yourself of course to survival.
You
were also looking at disease related symptoms that certainly appear to be a
very appropriate domain for establishing benefit. Yet you have said a couple of times something
along the lines of you weren't expecting or needing to prove superiority. Could you clarify the exact basis that you
were going to use these data to establish clinical benefit?
DR.
HAMBURGER: The discussions with the FDA
during the NDA review were that this trial would be sufficient and it was not
because of the limited patient population in the three-to-one randomization that there the DaunoXome was just there to
show the activity in the patient population.
I would like Dr. Teitelbaum to help further answer your question.
DR.
FLEMING: So at least the first part of
my question seems to be implicitly answered yes. Study 30-38 was the basis for establishing
benefit. Is that correct?
DR.
HAMBURGER: That's correct and survival
was not the primary endpoint, clinical benefit as defined and agreed upon.
DR.
FLEMING: So then that leads to the
second question which is the clarification as to exactly how we would judge
clinical benefit.
DR.
TEITELBAUM: Just to add to that. April Teitelbaum, Ortho Biotech. Reading from the letter from Sequus, the
purpose of the randomized comparison was to enable a blinded comparison to
minimize potential bias in assessment of clinical benefits. That was why the DaunoXome was the comparator
and was in the trial.
CHAIR
PRZEPIORKA: Just to summarize here, we
have a drug which looks like it has a very good response rate in these patients
but the problem in completing the commitment or getting a protocol together to
complete the commitment is that DOXIL appears to be already accepted in the
community and no one wants to do a randomized trial. HAART may actually confer a benefit on
Kaposi's but we're not certain about that.
Dr. Fleming.
DR.
FLEMING: Just to finish through this,
it's still not clear to me then what was our prospectively-defined basis for
judging whether this study was going to adequately establish clinical benefit. What was your target? What was your hypothesis? What was the threshold that had to be
achieved in order to conclude adequately that we'd established clinical
benefit?
DR.
ZUKIWSKI: We need the statistical
section of the trial.
DR.
HAMBURGER: You know Dr. Temple was the
one at the meeting with the sponsor at that time. Maybe you have some comments regarding that.
DR.
TEMPLE: It was a long time ago. Twenty years ago I would have remembered.
DR.
ZUKIWSKI: Dr. Teitelbaum has just
informed me that there was no defined threshold in terms of a statistical
parameter on improvement in the clinical benefit score from baseline.
DR.
MARTINO: Was this an equivalence trial
because it numerically doesn't look like it was?
DR.
ZUKIWSKI: No, there was never any
intention to compare the DOXIL to the DaunoXome arm. It was basically there to have an active
control to reduce any potential bias in evaluating the results.
DR.
HAMBURGER: And recall this was a double
blind trial so that was also important especially when one looking at symptom
improvement or changes that has always been guidance that the FDA has given to
sponsors.
CHAIR
PRZEPIORKA: So essentially it was
randomized Phase II trial.
DR.
ZUKIWSKI: Yes.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: I'm glad to see that the problem
is decreasing in incidence and I do understand that it's difficult to prove the
point when there is only small groups of patients. Are there parts of the world in which AIDS
related KS is still a pressing problem?
Have you explored the possibility of performing a Phase IV
post-marketing study outside the United States?
DR.
ZUKIWSKI: Yes, that is indeed the
case. There are areas throughout the
world where KS associated with AIDS is continuing to be a problem. However in order to adequately translate the
data that we would obtain in that population, we would have to have the same
standard of care delivered, i.e. anti-retroviral therapy to make it applicable
to the U.S. situation.
CHAIR
PRZEPIORKA: Dr. Pazdur.
DR.
PAZDUR: Can Dr. Krown perhaps comment on
KS in Africa if that is even a possibility?
DR.
KROWN: Actually a number of the
consultants raised that possibility.
Certainly to unequivocally look at the introduction of HAART alone in a
patient population that doesn't typically have access to those drugs and
compare that to HAART plus DOXIL would certainly answer the question of what
DOXIL adds to HAART but it is not really comparable to the situation that we
encounter in this country.
There
are also ethical considerations about bringing in HAART and DOXIL for the sole
purpose in Africa of proving a point and then not having a health care delivery
system that can continue to treat those patients. Although in an idealized world, that would be
the place to do it and that's certainly where you see a high incidence of KS
and a high incidence of very severe KS but it's not a practical solution.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: Just to follow that up, but
isn't one of the points here that this agent itself offers benefit to patients
if their retroviral therapy is not adequate or ideal? I understand that. Is not the argument that this agent helps
people who have KS and if it helps people who have KS irrespective of their
anti-viral therapy, would that not be an important thing to know?
DR.
KROWN: Of course it would be. You could take these data as evidence that
it's the case. The agency has said that
the introduction of HAART in some patients has so confounded the evaluation of
clinical benefit that it can't be determined.
But you could look at it another way.
CHAIR
PRZEPIORKA: I do have one question. Was there any correlation between response in
30-38 and decreasing viral load?
DR.
TEITELBAUM: Viral load was not looked at
routinely. It was not captured if the
individual sites did it.
CHAIR
PRZEPIORKA: Would it be possible to go
back and look at that data to suggest that if patients got a response without a
change in their viral load then it was probably not the HAART?
DR.
TEITELBAUM: We could attempt to do that
but I'm not certain as to where those documents would be. It's not in the database right now. That information was not captured by the
sponsor. So it would involve going back
and finding the charts on those individuals at those multiple sites.
CHAIR
PRZEPIORKA: Dr. George.
DR.
GEORGE: This example brings up at least
two interesting issues, one of which is going to be common in the next couple
of days. It is that the almost
conundrum, the wish to do accelerated approval, can jeopardize the successful
completion of the confirmatory studies which just emphasizes the point that was
made earlier by Dr. Pazdur and others that it would be very desirable to have
these studies underway.
In
fact, I would even emphasize that it would be at the time of the approval but
also have them be actually part of it.
As in a couple of examples we heard, the accelerated approval is part of
the study that then carries on to completion.
That's a moot point for this but it's a theme that is an issue.
The
second one for this particular example is a very unique setting. We should all be so lucky as to have the
diseases we're studying drop incidence by 80 percent but it also creates the
problem of course of small numbers but that the patients at least potentially
dramatically different than originally studied.
My conclusion here is that this is a nearly impossible situation in this
particular case. The first issue we're
going to have to come to grips with more in the next couple of days.
DR.
HAMBURGER: I'd like to make one
comment. We agree with you that the
conduct of the Phase IV commitment trials should be started before the
approval. This study could have been
started before the approval but it was dependent upon the availability of the
other agent which wasn't approved until later.
We started that trial as I mentioned earlier about four months after the
commercial availability of DaunoXome.
CHAIR
PRZEPIORKA: Dr. Pazdur, we talked
earlier about one potential scenario being there's no way we're going to be
able to ever prove what we need to prove under the current circumstances. Would it be just acceptable to allow the
public to know that everybody really believes it but we haven't proved it yet and
sign a consent form?
DR.
PAZDUR: We're going to have some
internal discussion on that point, Donna.
I'm not going to answer yes or no to that. Let me just emphasize this. Remember this was in the very early days of
accelerated approval. One of my reasons
of bringing this to you is not to embarrass anyone. It is basically to show that there has to be
a learning curve with anything that is out there. Given the history retrospectively and being a
Monday morning quarterback, it's obvious what should be done.
Our
goal here is we're going to work with the sponsor. Probably we will be calling some of you to
discuss further trial designs. If it is
possible, we may have to come to terms with this. I'm not ready to make that commitment nor do
I think Bob is at this time what our action would be on a situation where we
couldn't make a decision.
The
purpose of this is really as an illustrative example of exactly what I was
making the point of. These confirmatory
trials must be an integral part of a comprehensive program preferably started
long before back-up plans on the line here not waiting until something fails
five years after the fact. We have in
fact served our purpose here.
Again
we are using this as an illustrative example of a past problem. Granted, it still is an active problem. By no means, am I trying to shove this under
the carpet. But for us at this point in
a 20 minute discussion to solve this problem that the agency has been grappling
with over many meetings with the sponsor is probably not going to happen at
this meeting.
CHAIR
PRZEPIORKA: It's good to hear that there
will continue to be on-going discussions and support in order to help the
sponsor complete this commitment. Dr.
Redman is the discussant. If you could
summarize and give your insights regarding this problem.
DR.
REDMAN: Thank you. I was going to go through the questions that
the FDA asked and most of them have been answered. The document has accrual to on-going trials
and satisfactorily allowing for timely study completion. I look at this as the study was done. Unfortunately the sponsor was hit with the
fact of intervening therapy that brought up the question.
The
initial study was done. It was done to
the liking and specifics of the FDA.
After the study was done, something else had come and the baseline had
moved on these individuals. I would like
to hear what our Committee members feel about that.
CHAIR
PRZEPIORKA: Dr. Brawley.
DR.
BRAWLEY: I'm still stuck on how this
randomized Phase study which is terribly underpowered - some people call it a
randomized Phase II study - of DOXIL and DaunoXome, how you can do that trial
and not compare the two but use that trial for approval for DOXIL. I'm still lost at that. Can you explain that to me, Dr. Pazdur? I realize that nobody from Ortho Biotech and
nobody from the FDA was there in 1996 to make this decision.
DR.
PAZDUR: You hit the button on the head
but Bob was there.
DR.
TEMPLE: But I don't get the blame for
this. This is not the only trial done
that way. There was a period of time
when people did what you could call non-comparative comparative trials,
specifically underpowered trials, where the control group was really there to
show something about the population and what the overall response was and not
to provide a formal comparison. This was
popular in the communities. This was not
our invention.
I
really think few statisticians would be happy with this because what it's
actually doing is ambiguous. This is not
the only one. Maybe Grant
remembers. He's there chuckling at my
discomfort. That's what the point of it
was. The other drug tells you what's
going on in case it helps define the population a little bit and that's it main
function. Then you look at the results
almost as a single-arm trial but with some assurance that you have an idea
about the population. That's the best
I'm going to be able to do because it's not my favorite design.
CHAIR
PRZEPIORKA: Actually it is a favorite
one of mine. The reason it is simply
because of the situations like this where standard care, supportive care, all
of that changes the natural history of the disease. If you power your Phase II study in order to
look at an outcome theoretically based on some historical control, you may not
get the right answer if your current population is not like that. So you can't go into a good Phase III trial
without that knowledge. This is an
interesting situation where in fact the HAART did in fact change the natural
history of the disease and the "compared to arm" showed us that
responses were still good even with DaunoXome.
DR.
PAZDUR: This has really demonstrated a
lot of examples, the change of therapy, a learning experience.
If we take as a learning experience of why to do these trials early,
obviously there can be a change in therapy.
That's even another reason. You
could have the introduction of the agent when it becomes available commercially
interfere with the study.
Here
again I think two good examples of why this premise that we are trying to
develop really hit home and enunciate and not to beat the drum any further of
having these trials on-going clearly rings out here. Just to reiterate this is history. Going back is sometimes hard to
construct. It probably is not something
that we would go ahead with this trial design at this time in this disease.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: Two things. The SEER data as I would take is striking
evidence that HAART has influenced also in a preventive fashion Kaposi's
sarcoma treatments as well as incidence.
It seems to me as Dr. George has pointed out this is a problem to
have. When the regulations were drawn,
it wasn't anticipated that a cancer would go away as a problem.
My
summary statement would be in this indication we ought to declare victory and
move on with something to other problems that are more public health
issues. Whether the regulations
anticipate that phase that confirmatory trials will never be done, I would say
okay but that's probably not important in this indication.
DR.
REDMAN: But there is data that suggests
that DOXIL is still being used out there even though the incidence of Kaposi's
sarcoma, AIDS related, is decreasing.
The information I have is that the drug is still being used. So it's still a problem. It may not be as massive a problem as it was
10 years ago or even five years ago but it's still a problem. Does DOXIL add anything or can it be proven
to add anything to the treatment of AIDS related Kaposi's.
DR.
BLAYNEY: We have heard experts and I
haven't seen an AIDS-KS in probably eight or 10 years. I used to see a fair amount. It's probably not a major public health issue
and probably the study won't ever be able to get done.
DR.
REDMAN: Any study or a Phase III
randomized trial?
DR.
BLAYNEY: I'll bet you any study. Unless something dramatic happens with HIV
resistance to HAART, then you could conjure up a lot of possibilities that
would make the underlying immunosuppression and cancer susceptibility
different. It may never be doable. Any study.
CHAIR
PRZEPIORKA: Ms. Mayer.
MS.
MAYER: It occurs to me that there may be
some future applications in a way of what we learned from this experience. If research proceeds as we would like it to
in all cancers, we will be seeing more in the way of targeted cytostatic
treatments becoming available. Yet there
may still be a need for rapidly-acting cytotoxic drugs to get really aggressive
disease under control. I wonder if we
can't think ahead about accelerated approvals for cytotoxic drugs bearing this
in mind. This doesn't seem to me like a
completely unique situation just in terms of how the disease behaves.
CHAIR
PRZEPIORKA: Dr. Brawley.
DR.
BRAWLEY: I suspect I'm going to be
saying this quite a bit over the next two days.
One of the things that perhaps we should consider which is a compromise
in scientific principles is going and looking at the pediatric model or
registration trials as opposed to the FDA use of the word for
"registration trial" and maybe merging the two.
It
would be interesting to have data on three to five hundred Kaposi's sarcoma
patients who are all treated with this drug in the prescribed way. It would be interesting just to know what
happened to those patients, how many of those patients had disease that
regressed, how many of those patients had improvement in quality of life and on
the other hand, how many didn't. Perhaps
that's the only way that you are going to be able to truly assess the
drug. Then of course it's not going to
be a true assessment because it's a Phase II type of approach.
There
have been a number of things that we've done in American medicine over the last
100 years. Many of us would probably
especially many of the more vocal of us bear to read some of that medical
history about how things like bone marrow transplant for example which is not a
drug but the use of a number of drugs for breast cancer seem to be working but
ultimately in randomized trials did not work.
I'm
always struck by the fact that we did the Halsted radical mastectomy for 75
years because it seemed to be the right thing to do. Only after the randomized clinical trials
were completed which were very difficult to do that we realized that for 75
years we did the wrong thing to women.
There's a whole long laundry list of things that seem to be the right
thing to do after essentially a Phase II comparison that turned out to be the
exact wrong thing if you were truly the advocate of the patient. But in this instance, we do need a large
Phase II-ish, after-marketing registration trial in the pediatric model. Thank you.
DR.
PAZDUR: Just to add to Otis's litany,
the Prempro example is the current one.
You forgot it.
CHAIR
PRZEPIORKA: Dr. Redman.
DR.
BRAWLEY: How long did we give Premarin
and Provera because it was good for women.
Then after the randomized clinical trial, we found it caused heart
disease. It prevents colon cancer but
also causes breast cancer.
DR.
REDMAN: I think Dr. Brawley brought up
the very final point at least which is what alternative design should be
considered. As one of the questions that
I asked about the Phase II design, the cooperative groups have shown in this
disease that they are not going to do a Phase III trial in AIDS related Kaposi's
sarcoma. If the cooperative groups
aren't going to do it, there isn't going to be a consortium of groups that are
going to be able to do it. The sense I
had from the expert panel that was convened by the sponsor was that some type
of Phase II registry trial with defined endpoints would be valid. What those endpoints were with discussion
with the FDA could be delineated and become acceptable for final approval.
CHAIR
PRZEPIORKA: Dr. Pelusi.
DR.
PELUSI: Since we're throwing out just
ideas and trying to brainstorm when you look at patient advocacy groups and you
look at their tight network, the question becomes how can we involve them in
whether it's looking at long term survival in terms of a registry and what data
they may actually be able to have as well as looking at our own SEER registries
and what is put into that. Now they are
either alive or maybe they have the disease but again some of those other
indicators may be helpful in trying to open that box and say where can we get
data not only now but also long term.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: I would certainly agree that
one of the benefits of reviewing this experience is to learn how we can more
effectively implement the accelerated approval process in the future. At the same time, we have to assess where we
are today on this application and what is the proper interpretation and what
are the proper next steps to be taken.
I
would agree with the FDA judgment made on July 31, 2002 looking at these data
that the role of DOXIL is unclear in the presence of HAART. Certainly in the nature of this trial and
these results, I would arrive at that same conclusion. The question then is what will serve as a
basis to allow us to in a timely way reliably establish whether there's
clinical benefit. We're also hearing that
there is considerable uncertainty about where we go from here.
What
is the unmet need? Certainly the unmet
need in 1995 differs from what the unmet need is today in this setting. The nature of this unmet need has radically
changed, HAART being one of the major reasons for that not only influencing
incidence but also overall consequences of Kaposi's. In addition to that, there have been two
other approvals in 1996 and 1997 of Doxorubicin liposomal and Taxol.
So
the question is what is the basis at this point for continuing the accelerated
approval. If we look at the intentions
in the spirit of the regulations, it was these procedures are intended when
drugs provide meaningful therapeutic advantage over existing therapies. It's also made clear later on that the fact
that an agent is accepted is not a basis for continuing marketing. So we clearly have an accepted agent.
We
have one for which there is a judgment that the data that was intended from a
pivotal study does not provide adequately interpretable evidence to establish
benefit on symptoms. We didn't just
require survival. We looked at
symptoms. We don't have an adequate basis
to think of how we would get a reliable estimation of efficacy in a timely
fashion. An unmet need has been
radically changed. I would ask then in
the spirit of accelerated approval how does one justify continuation and not
withdrawal.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: I didn't understand one thing,
Tom. My understanding is that while the
frequency of KS is way down there still are some people who despite HAART get
it. Why isn't that the unmet medical
need even though it's a much smaller population than you had before?
DR.
FLEMING: The fact that people get an
agent doesn't in fact establish the relevance and importance of continuing to
make its availability.
DR.
TEMPLE: No, we're just talking about
whether there's a need.
DR.
FLEMING: Whether this can be studied and
evaluated is another question but what I said is the nature of the unmet need has
radically changed. Is there and to what
extent would you judge it today to be an unmet need in view of HAART which has
radically changed incidence and outcome and in view of two other approvals of
other agents?
DR.
PAZDUR: I would still consider that the
nature and degree of that unmet medical need may have decreased. But to say that it's non-existent, I think
would be inappropriate. Perhaps somebody
that treats AIDS, Dr. Krown, could comment that. I feel somewhat incompetent to do that since
I don't see the disease. To say that
AIDS-KS is not an unmet medical need would be inappropriate.
DR.
FLEMING: Let me just clarify the nature
of my comment. It is that the level of
unmet need in 1995 compared to where we are today has substantially changed.
DR.
PAZDUR: So it's a magnitude difference.
DR.
FLEMING: It's a magnitude issue. Then the essence of my question is at
whatever level of unmet need there needs to be a strategy, a timely
ascertainment or evaluation, of clinical benefit. The study that was put forward we can
criticize today as to whether or not it logically could have been on that basis
of what the reality is today.
The
FDA, and I would agree with their judgment in 2002, judged that this did not
provide an adequate basis for establishing benefit. There isn't a clear cut plan in place to
allow us to now move forward from where we are to achieve such a reliable
assessment in a timely way. In the
spirit of the accelerated approval regulations, is this not then a basis for
withdrawing approval?
DR.
KROWN: Dr. Krown would love to
comment. Actually I would like to
comment on a number of things. I would
love to show you some pictures because there are a lot of people in the
audience who know theoretically what we're talking about but actually haven't
seen this. In this case, sometimes the
pictures are worth a thousand words.
Clearly not all of the patients have disease of this severity. Why don't you move ahead to 117? I just want to show a couple of pictures.
I'm
just going to show you pictures of KS that has presented in the era of HAART
therapy. This is disease on the inner
thighs of a patient who in this case was avoiding being treated for both HIV
and KS. When he couldn't stand it
anymore, he showed up for treatment.
This was early enough on so that nobody had even reported KS regression
with HAART but you can't say to a patient like that let's give you HAART and
maybe in four or six months you might be better because we knew that we had a
drug that was likely to help him. He
received both HAART and DOXIL and did respond.
Move
on to the next one. Other patients
present having been on HAART but have been intolerant or noncompliant with
their therapy in a poor control of their HIV infection and have advanced
nodular disease that causing edema which you can see there and ulceration and
pain.
The
final one. I hate to do this to people
before lunch but this is actually the foot of a patient who just refused to
take any oral therapy. He had his own
reasons for this. I don't presume to
tell him that he couldn't do that. He
walked into my office with that foot. We
treated him with DOXIL. The next slide
after just a few doses shows what happened.
I'm not saying that these are all the typical patients that presents
with KS today but I'm saying that these are the patients for whom there is a
need.
I
would also like to address two other things, one of which is the reason why
there is a preference for DOXIL in the community. Unlike the other approved agents, DOXIL needs
to be given less frequently. Both Taxol
and DaunoXome are typically given every two weeks whereas DOXIL is generally
given every three weeks which is a convenience in quality of life factor for
patients.
When
you compare a liposomal Anthrocycline to a taxane, there is little or nothing
in the way of neuropathy, little or no hair loss. There are many important quality of life
issues for patients that makes them even more than their physicians choose a
drug like this compared to others that are out there in the community.
Finally
what I would like to say is that we're dealing with an extraordinary
heterogenous group of patients who present with far enough advanced disease so
that clinical benefit can actually be assessed.
Patients with lesser degrees of KS may not need chemotherapy at all or
may not have specific symptoms other than I don't like the way my skin looks
which is hardly something that you can assess in an objective way.
So
we have patients who have never been treated for their HIV disease, patients
who failed on therapy because they have a resistant virus, patients who are
intolerant, patients who are noncompliant.
Controlling for all those factors while at the same time evaluating the
effects of a drug for KS is extraordinarily difficult. So this the challenge we are facing. But, yes, there are those patients still out
there.
DR.
PAZDUR: I want to come back to Tom's
point because it needs to be addressed.
One of our reasons of bringing this up obviously is to give public
disclosure to what is going on with these accelerated approvals. You do represent a valid viewpoint. Obviously there are other viewpoints that we
have heard from Committee members that do not necessarily correspond or
correlate with your viewpoint.
This
is going to be a point of on-going discussion.
Remember this is a process. Your
point is well taken. I'm glad that it
has been brought out in a public forum with the sponsor hearing it. Nevertheless there are other viewpoints that
have been expressed here.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: We're sitting here saying that
1500 patients is a tiny number when we have had drugs approved for diseases
like GIST that's required far fewer numbers of patients. Those are really rare entities. What I'm suffering here is a lack of
knowledge because I assume that there are certain subpopulations of patients
who are not going to respond to HAART for their KS. It's hard to approve a drug just for patients
who refuse to take oral therapy or patients who decide to wait too long.
If
we could identify based on whether it's this Tandem registry bank or what have
you, a group of patients that either won't or can't respond to HAART and then
do a Phase II trial in that group of patients.
Then if there are enough of them around that we probably could get some
useful information as to whether this drug is active or not sufficiently to
meet the criteria to approve it.
We
don't need a Phase III trial when we have situations like this. It would be impossible to do it but there are
those patients out there and 1500 is not a small number when all you probably
need is 100 of them. The AIDS activists
have been very effective in the past in mobilizing patients to participate in
clinical research. If we could get their
help, perhaps we could get the study done.
DR.
PAZDUR: And response rate with its
ensuing cosmesis effect would be clinical benefit.
DR.
TEMPLE: We've totally agreed that the
small number of people with the disease is not a basis to deny it.
You can be an orphan and still have accelerated approval. That's okay and that happens and it's
supposed to happen.
DR.
CHESON: But the point was that not from
your perspective of it but there are enough patients out there. Fifteen hundred is really not a tiny number. There are enough patients out there to do a
trial. Just to say there are only 1500 a
year, that's not justification for not doing a study because there are far
fewer hairy cells and there are three drugs approved for hairy cell. Yes, remember those days. And GIST, etc. and the pediatric diseases as
well from my friend here on my left, fewer patients have been required to
approve drugs.
CHAIR
PRZEPIORKA: Dr. Redman.
DR.
REDMAN: Let me go back to the original
confirmatory trial and just ask the FDA a question. I take the sense of the problem was with
HAART. Was there a problem with their
clinical benefit endpoints looking even back in retrospect?
DR.
PAZDUR: Actual endpoints, no, because we
would expect a response rate with cosmesis in a cutaneous disease. We've done this not only for KS but cutaneous
T-cell lymphoma, etc. to be a clinical benefit.
DR.
REDMAN: So the endpoints are still valid
here.
DR.
PAZDUR: Correct.
CHAIR
PRZEPIORKA: Dr. Temple, Dr. Hamburger,
do you have any other questions for the Committee? Otherwise, I will let you all take a break
for 10 minutes. Off the record.
(Whereupon,
the foregoing matter went off the record at 10:44 a.m. and went back on the
record at 11:01 a.m.)
CHAIR
PRZEPIORKA: On the record. We're called to order here. If we could all take our seats.
DR.
PAZDUR: I just want to bring a degree of
clarification in the interpretation of the regulations here that is very
important and could have gotten misunderstood or misconstrued. It is the idea of judgment that the
regulations give us. That is the use of
the word "may." The
regulations state that we "may" ask for these confirmatory
trials. It doesn't say that we
must. However when we ask for them which
under my reign I assure you will happen, they are required to do them.
Also
if the application or the clinical confirmatory trial fails to show clinical
benefit, we "may" then move for an action to take the drug off the
market or to remove the application.
That issue is an area that gives us judgment so we don't need to have a
reflex situation. You fail therefore you
must come off.
As
in any regulatory judgment, we have to take a look at the total picture. Obviously there are the clinical trials that
are being undertaken for confirmatory trial.
There are other evidence of a drug that are in cooperative groups, that
are in single-institution groups, etc. that could come in to bear in making a
regulatory decision. The principle that
I want to get across here that might have been lost is this area of clinical
judgment. It is not necessarily a
knee-jerk reaction.
CHAIR
PRZEPIORKA: Thank you. Going on to the next session, we will start
with the Conflict of Interest Statement please.
DR.
FLEMING: Donna, could there be a
question on this clarification? Is there
time?
CHAIR
PRZEPIORKA: A short question or a
question that will have a short answer.
DR.
FLEMING: Okay. The first "may" that you said I was
not sure that I understood. The regs as
I understand them say that if the approval is based on a surrogate endpoint,
the applicant will be required to conduct clinical studies necessary to verify
clinical benefit.
DR.
PAZDUR: The rule actually says
"may" unless you are looking at something different.
DR.
FLEMING: I'm looking at page 3, section
C, "Post Marketing Studies."
We can come back to that.
DR.
TEMPLE: I'll find it.
MR.
OHYE: I think he's looking at the
preamble and not the regulations.
DR.
TEMPLE: The regulation actually says
"may" but I'll check and make sure.
I don't want to tell you something that's not true.
CHAIR
PRZEPIORKA: Ms. Clifford.
SECRETARY
CLIFFORD: Thank you. The following announcement addresses the
conflict of interest issues with respect to this portion of the meeting and is
again made part of the record to preclude the appearance of a conflict. To determine if any conflict exists, the
Agency has reviewed the submitted agenda for this meeting and all the relevant
financial interests reported by the Committee participants.
The
Conflict of Interest statute prohibits special Government employees from
participating in matters that could affect their personal imputed
interests. However the Agency may grant
a waiver if the need for the individual service outweighs the conflict created
by the financial interest.
Accordingly
waivers have been granted to the following individuals: Dr. Douglas Blayney for owning stock in the
sponsor worth from $25,001 to $50,000; Dr. David Kelsen for owning stock in two
competitors each worth from $5,001 to $25,000; Dr. Thomas Fleming for serving
on two data monitoring committees for a competitor which for this unrelated
activity he receives from $10,001 to $50,000 a year; Dr. Scott Lippman for
serving on a competitor's speaker bureau for which he received $10,000 a
year. A copy of these waivers may be
obtained by submitting a written request to the Agency's Freedom of Information
Office, Room 12A-30 Parklawn Building.
In
addition, we would like to note that George Ohye is participating in this
meeting as the Acting Industry Representative.
Mr. Ohye would like to disclose that he owns stock in the Johnson &
Johnson and in a competitor. He receives
retirement pay from the sponsor. His
wife works for the sponsor. Within the
past year, he consulted for the sponsor.
In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participant should exclude himself or herself from such involvement and the
exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose any
current or previous financial involvement with any firm whose products they may
wish to comment upon.
CHAIR
PRZEPIORKA: Thank you. If the new members of the division could
introduce themselves to the panel and the sponsor please.
DR.
WILLIAMS: Grant Williams.
CHAIR
PRZEPIORKA: We'll start with the
presentation by Dr. Hamburger of Johnson & Johnson regarding NDA 50-718,
DOXIL for treatment of metastatic ovarian cancer in patients with disease that
is refractory to both Paclitaxel and platinum-based chemotherapy regimens.
DR.
HAMBURGER: Thank you and again good
morning. For the record, my name is
Steve Hamburger. I'm an employee at
Johnson & Johnson Pharmaceutical Research and Development. My goal is to provide you with background
information regarding the actions taken to fill the Phase IV commitments for
DOXIL in treatment of patients with ovarian cancer. We hope that this information will facilitate
your discussions to provide guidance on the accelerated approval process in the
Phase IV commitments that will allow conversion from accelerated to full
approval.
I
will discuss some of the challenges we have encountered in conducting Phase IV
commitment trials in patients with this disease. Some of the challenges may be specific to
this disease but others may be applicable to other diseases. With me today to answer your product specific
questions are my colleagues, Drs. George, Mohanty, Teitelbaum, Tonda and
Zukiwski.
DOXIL
is indicated for "The treatment of metastatic carcinoma of the ovary in
patients with disease that is refractory to both paclitaxel- and platinum-based
chemotherapy regimens. Refractory
disease is defined as disease that has progressed while on treatment, or within
six months of completing treatment."
The
original Phase IV commitment trial was agreed upon with FDA. This trial designated as Study 30-49 was
on-going as a Phase III study before the NDA was submitted. Later in the presentation I will provide more
details regarding this study as well as its current status which is now
complete and the planned final survival analysis is underway.
A
second Phase IV commitment study referred to as SO200 is currently enrolling
patients. The FDA has already informed
us that this study will fulfill the Phase IV commitment to convert DOXIL from
accelerated to full approval. The
primary endpoints for both studies is overall survival.
There
are some challenges surrounding the Phase IV commitment trials. The time to reach the survival endpoint in
the original Phase IV commitment trial 30-49 was longer than estimated. For the second commitment trial, multiple parties
were involved in its finalization and implementation.
There
is competition for accrual to the second commitment trial. This was far less a challenge for accrual for the first commitment trial
which completed accrual in 1999. Now
there are other drug either approved for these patients, prescribed or being
actively investigated in this patient population.
Finally
U.S. physicians frequently prescribe DOXIL to treat patients with ovarian
cancer. Thus the commercial availability
of DOXIL provides patients with an alternative source of drug outside the
clinical trial setting.
In
November 1998, DOXIL received orphan drug designation for this indication and
this was one month before the sNDA for ovarian cancer was submitted to the FDA.
In
June 1999, the ODAC recommended that DOXIL receive accelerated approval. Later that month, FDA approved the drug for
this indication. The sNDA contained data
from three Phase II non-comparative studies in patients with relapsed or
refractory ovarian cancer. The primary
endpoint was response rate and the dataset contained efficacy and safety
information from 176 patients. In
addition, data from the interim analysis of the on-going Study 30-49 was
provided for review. In approval letter,
FDA acknowledged that completion of Study 30-49 was the Phase IV commitment.
The first patient was enrolled in Study 30-49 in
May 1997 and the last patient enrolled was about two years later in March 1999.
This
is a randomized Phase III trial of DOXIL versus Topotecan in ovarian
cancer. Topotecan had been approved in
May 1996 about one year before the study started comparing it to DOXIL. The objective of Study 30-49 was to compare
the efficacy and safety of these two drugs.
The study population was patients with relapsed ovarian cancer following
failure with platinum-based chemotherapy.
The sample size was 474 patients.
The
stratification was based upon platinum sensitivity and bulk of disease. In this slide you can see the two dose
schedules for DOXIL and Topotecan. The primary
endpoint of the study was time to progression.
Secondary endpoints included objective response rate, response duration,
survival and safety. The original design
of this study was non-inferiority of DOXIL to Topotecan.
In
June 2000, ALZA provided data from the planned end of treatment analysis. The timing of this analysis was when all
patients had received a minimum of 24 weeks of therapy, six or eight cycles
depending upon the treatment arm or disease progression. The analysis did not demonstrate superiority
in time to progression.
FDA
requested superiority between treatments for conversion to full approval. However there was a significant survival
advantage of DOXIL compared to Topotecan in the platinum-sensitive group. This was a subgroup analysis of a secondary
endpoint. At this time about half of all
patients were still alive.
This
is the data for the primary endpoint proposed in the trial which was time to
progression and the number of patients per treatment arm and their platinum sensitivity. As expected, time to progression for platinum
sensitive patients is higher than platinum-refractory.
Now
I present the results for the survival analysis at this time point. The 26 weeks improvement in survival in the
platinum-sensitive was extremely encouraging.
This is the data of the percentage of patients that had adverse events
either Grade I, II, III, or IV for each of the treatment groups.
At
the June 2000 meeting, FDA agreed to a final survival analysis to be performed
when a percentage of the 474 randomized and treated patients died or were lost
to follow-up. Ninety percent events were
chosen to provide adequate power for survival analysis on all patients enrolled
in the study. Thus the protocol was
amended to reflect this change. In
addition, FDA requested a second protocol to prove the clinical benefit of
DOXIL in patients with ovarian cancer be provided.
This
protocol was submitted by ALZA one month later.
The design was a comparison of DOXIL and carboplatin versus carboplatin
alone in platinum-sensitive patients with recurrent epithelial ovarian
carcinoma after failure of initial, platinum-based chemotherapy.
In
the last quarter of 2000, there was dialogue between ALZA and the FDA regarding
the protocol design of the second Phase IV commitment trial. Then in January 2001, discussions between
SWOG and ALZA began for this to be a SWOG trial. These discussions included agreement with FDA
on the design of the Phase IV commitment trial.
The protocol was submitted to the FDA in December 2001.
Briefly
SWOG SO200 compares overall survival as the primary endpoint between the two
treatment groups. Secondary endpoints
include progression of free survival, confirmed CRs, time to treatment failure
and toxicity. Patients with recurrent disease or disease progression with
a progression-free and platinum-free interval of six to 24 months after
completion of first line platinum-based chemotherapy will be enrolled. The target is to enroll 900 patients.
This
is a randomized, intergroup, open-label study comparing these two
treatments. SWOG activated this protocol
last August and the first patient was enrolled one month later.
I
would like now to update you on the status of the original Phase IV commitment
trial Study 30-49. As you recall, FDA
agreed to a final survival analysis performed when 90 percent of the 474
randomized and treated patients had died or were lost to follow-up. We are currently performing the analysis of
the final survival data. When that is
available we will consult with the primary investigator and provide this data
to the FDA for their review.
I
would now like to conclude with some of the issues or challenges with
conducting the Phase IV commitment trials.
After the end of planned treatment analysis for Study 30-49, the primary
endpoint for was modified to become overall survival. A 90 percent event endpoint was chosen which
originally was thought would occur about 12 months later. However the time to reach the 90 percent
endpoint in Study 30-49 was greater than 3.5 years. Thus patients on both treatment arms lived
longer than originally anticipated. This
again was great news but did not allow for the rapid completion of this
commitment.
Finalization
and implementation of the second Phase IV commitment trial took some time. Multiple parties were involved in the
finalization in design of this study.
Again this is a 900 patient study.
This is one of the largest studies in patients with relapsed ovarian
cancer that had ever been conducted. In
addition, there was some time delay when clinical responsibilities were
transferred within our company.
Competition
for accrual is always an issue. There
are many on-going clinical trials competing for the same patient
population. In addition, DOXIL can be
prescribed to patients outside the clinical trial setting.
In
summary, there are two pathways that could lead to full approval for DOXIL in
treatment of patients with ovarian cancer.
One is the original Phase IV commitment trial, Study 30-49, that started
before the NDA submission and enrollment was completed prior to its accelerated
approval. The design was acceptable for
conversion to full approval. The planned
survival analysis is underway and we will provide this information to the
investigator and FDA when it is available.
The
second trial is on-going and the study design is acceptable as a Phase IV
commitment study. We are committed to
completion of the analysis for Study 30-49, discussion with FDA and others
including yourselves regarding the results from the final survival analysis as
well as completion of Study SO200. Thank
you.
CHAIR
PRZEPIORKA: Thank you, Dr.
Hamburger. Dr. Williams, do you have any
comments for the Committee?
DR.
WILLIAMS: I just want to provide a
comment about the original Phase IV trial.
This was an unusual circumstance where we did accelerated approval and
then we looked at the trials that were on-going and noted that particular trial
was in progress. We looked at the design
of the trial. It was a direct comparison
to Topotecan. It had the potential to
show superiority in clinical benefit.
But
in our analysis of its design as a non-inferiority trial, there was not
sufficient evidence regarding the precision of the benefit of Topotecan to
allow it to be a non-inferiority trial.
We didn't know the confidence intervals of the Topotecan effect. So we did not believe that it would serve in
that way.
Perhaps
if we were to go back today and do it, we'd say okay go ahead and start another
trial and then we'll look at this one too.
But what we chose to do was to say if it shows superiority within the
next year or so when the data were to come in, then we would accept that for
clinical benefit. But if it doesn't,
then you need to go on and do another study.
That's the way it happened. It
wasn't necessarily identified as the accelerated approval trial when it came
in. It was just noted that it was there
and the results were to be available soon.
CHAIR
PRZEPIORKA: If I can summarize the
issues, they are that again DOXIL is already out there and people are using
it. There are competing interests in new
drugs coming out that will slow down accrual to the second protocol. The good news/bad news is survival in the
first protocol is longer than expected or just waiting to get to the endpoint a
little bit longer than we would expect to.
Comments or questions from the Committee? Dr. Martino.
DR.
MARTINO: Actually a question. Not knowing the survival results of the two
trials but assuming that it does in fact demonstrate superiority, is there
still interest for the SWOG trial to continue or how will you handle that
issue?
DR.
HAMBURGER: I'll let my clinical
colleagues answer that question.
DR.
ZUKIWSKI: We're committed to completion
of the SWOG trial. It doesn't matter
what the results are. That trial will
continue and we will continue to support it and supply that data to the FDA as
it matures.
DR.
MARTINO: And that's an intergroup sort
of design in participation rather than purely SWOG, I assume.
DR.
ZUKIWSKI: Yes.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: You are talking about a
survival benefit on your 30-49 trial.
The survival as we've heard alluded to can be influenced by crossover to
another treatment. I suspect that's
happened a fair amount on both arms. Are
you capturing that data as part of the study?
DR.
HAMBURGER: We are not capturing
subsequent therapy.
DR.
BLAYNEY: So it sounds like there's great
danger that you may have a null result.
DR.
HAMBURGER: There has been previous
communications with other products regarding the effect of subsequent therapy
on the survival endpoint. I don't know
if Dr. Temple or Dr. Pazdur want to discuss that. I know this has come up in discussions of the
ODAC with other molecules about the effect of subsequent therapy on survival
endpoint.
DR.
TEMPLE: I'm sure Rick will want to
comment more. The Committee when asked
on several occasions has urged the overall survival be the endpoint. My own personal worry and we'll eventually
come back to you with this is that if the thing you crossover to has
significant activity, it has to be a bias toward equivalence. I'm just worried about what that means. It's not clear you can ethically prevent it
and it's not clear what it does to the survival endpoint. But that's a longer discussion. I think we need to do some modeling and other
stuff and see what it is but we are worried about it.
We've
seen trials where there was a clear effect on time to progression and clearly
less effect on survival. That's a
predictable result if what you crossover to is active. So we are worried about it but don't have an
answer yet.
DR.
WILLIAMS: In general we would like the
data collected. I'm not sure what we
would do with it. I flirt when I heard
the discussion back and forth but it would be prudent to collect the data. Obviously this wasn't your primary
endpoint. Time to progression was and
therefore it probably wasn't written into the protocol.
DR.
FLEMING: Just a comment on this very
point. I think we have to distinguish
between crossing in to the experimental therapy versus what we might call
crossing in which just means getting access to what would be both ethically and
scientifically appropriate which is effective, supportive standard of care.
If
in the SWOG trial which is carboplatin plus DOXIL versus just carboplatin if we
cross in at progression on the control arm, that's problematic. In fact, many of us would argue that it's
begging the very question we're trying to ask.
That's answering a question immediate versus delay when we really want
to answer the question treatment versus not.
On
the other hand, if we are looking at for example in the 30-49 trial DOXIL
versus Topotecan and it's DOXIL followed by best possible management
versus Topotecan followed by best
possible management, I don't call it a bias if supportive care ultimately
yields a result that suggests there's no difference. The strategy of initiating DOXIL versus the
strategy of initiating Topotecan followed by best possible management in that
case if it shows no difference is the truth.
DR.
TEMPLE: I don't agree with that. I'll tell you why. You are the Oncologists so you can figure it
out. In the long run all survival curves
go to zero and you don't see anything.
What you want to know is whether a response with this drug actually has
clinical benefit. The fact that you can
obliterate that by giving everybody the same good therapy afterward doesn't
tell you that this drug doesn't have the desired effect on things. So I really do think you want to know. I'm not quite sure how you find out because
you can't stop people from using and crossing over to a marketed drug.
DR.
FLEMING: It's apparent that this debate
will have to be answered off line. It's
much longer than just this time allotment.
The immediate point though is the fact that curves go to zero is not
relevant to the issue. It's how quickly
they go to zero is the point.
Ultimately
I would say I want to know what's the clinical relevance of a strategy starting
with DOXIL versus a clinical relevance of a strategy starting with an
alternative regimen. Ultimately, does
that translate into clinical benefit for the patient, i.e. survival being one
of those measures? We'll carry this
discussion on later.
CHAIR
PRZEPIORKA: Dr. George.
DR.
GEORGE: I had a question of
clarification concerning the data from interim analysis presented back in
1999. The accelerated approval. I'm just curious about how that works and how
that fit into the decision at that time for accelerated approval.
DR.
HAMBURGER: Let me clarify and say that
the data I showed you in the treatment analysis occurred after the
approval. There was interim data that
was provided to the FDA during the review on 30-49 and it looks like Dr.
Williams wants to address that one.
DR.
WILLIAMS: We had the final analysis for
the primary endpoint of time to progression.
Right?
DR.
HAMBURGER: That's correct.
DR.
WILLIAMS: So in some sense, it wasn't an
interim analysis. You are looking at
survival after this subgroup analysis you believe. I just want to make a comment. It didn't seem that the subgroup had a
superior time to progression just survival so that makes it more likely in my
book that it's chance finding.
DR.
GEORGE: Was this known? Is the first time anybody is hearing about
this?
DR.
WILLIAMS: You're talking about the
subgroup analysis.
DR.
GEORGE: Yes.
DR.
WILLIAMS: Yes we did not buy that.
DR.
GEORGE: The other issue I have is
concerning the length of time until you get 90 percent of the events. Is it really surprisingly long? If you had a median survival of one year and
even if you started everybody at the same time, it would take almost three and
a half years to get 90 percent of the events.
DR.
HAMBURGER: I'd like Dr. Mohanty to
answer that question.
DR.
GEORGE: Is survival really better? It takes a long time to wait. It's just turning light bulbs and waiting
until they all fail.
DR.
MOHANTY: It was long but I don't think
it is longer than what was totally unexpected.
At the end of the planned analysis which is two years, at that time 50
percent events or deaths had happened.
So it was expected to take long.
It was a little longer than what was expected but survival takes a long
time.
DR.
GEORGE: Yes, I think it's a little
misleading to say that survival is good.
It just takes a long time. The
extremes take a long time to observe.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: Just to clarify Dr. Fleming's
point. Best supportive care after failure
of DOXIL often is Topotecan so there's a cross-in here.
DR.
FLEMING: It's the opposite though. I have no problem with the experimental
leading to standard. It's the opposite
direction. It's the standard than having
a cross-in into the experimental is the problem.
DR.
BLAYNEY: Because of non-overlapping
toxicities, women get the opposite treatment very commonly I suspect.
DR.
HAMBURGER: Just remember that both drugs
were approved at that time so they were available for patients to receive either
drug as subsequent therapy.
CHAIR
PRZEPIORKA: Ms. Mayer.
MS.
MAYER: Just a question about the history
of accelerated approval of DOXIL for this indication. What was it about the research at the time
that caused you to bring this discussion to ODAC as I understand it was
discussed here?
DR.
WILLIAMS: Right. It met pretty much our standard setting for
accelerated approval as a drug that has some activity in a setting where there
is no available therapy. So it had a 15
to 20 percent response rate. It was
actually zero in Europe if I recall.
They had a Phase II study in Europe that was zero but it was higher in
the U.S. So it showed activity and was
considered before the Committee to be reasonably likely to predict clinical
benefit.
MS.
MAYER: Yes, but you brought it to the
Committee. There are some accelerated
approvals you don't bring to the Committee and some you do. I'd like to understand more clearly what
criteria you looked at.
DR.
WILLIAMS: Of course there is the
history. There are different division
directors. There's different types of
applications. At that time, we brought
almost everything to the Committee. We're
being a little more selective now because we're getting a few more
"me-too" type drugs that really don't require the Committee's
judgment. At that time, we were bringing
essentially every application in and this was an accelerated approval. The setting accelerated approval lends itself
in some circumstances where you have somewhat borderline evidence, then this judgment
of what's reasonably likely by a group of experts fits well for the Committee
in cases where it's borderline.
CHAIR
PRZEPIORKA: Dr. Martino.
DR.
MARTINO: A question to the FDA. If the first of the two trials demonstrate a
survival advantage, at present does that then provide enough data in your mind
for full approval or is the second trial still a requirement?
DR.
WILLIAMS: The regulations basically
state that the sponsor will supply evidence that the drug provides
benefit. At the time that the FDA
determined that there's sufficient benefit to meet our approval standard, then
we would act at that time.
CHAIR
PRZEPIORKA: Dr. Brawley is the
discussant for this question and will give his comments.
DR.
BRAWLEY: Thank you very much. So far and perhaps, Dr. Hamburger, you can
help me if I were to summarize, you had three Phase II clinical trials that
showed efficacy with the drug and that was used for getting accelerated
approval. At the time of accelerated
approval, Trial 30-49 was already enrolling patients. That was a trial that looked at DOXIL versus
Topotecan in women who had been treated with just platinum in the past.
The
endpoints for Trial 30-49 changed over time.
One question I have is did the purpose of the trial change. Was it initially started as a trial to show
equivalence and then seems that it changed into a trial to look at the
possibility that DOXIL might be superior to Topotecan?
DR.
WILLIAMS: I could probably address that
in some ways. The sponsor was planning
to do non-inferiority studies. If I
recall, there's a lot of back and forth about FDA's lack of comfort with the
demonstration of Topotecan as an active control for an equivalent study or
non-inferiority study. At the time it came up for accelerated approval, we told
them that regardless of what you've planned we will only evaluate it as a
superiority study. I think there was
probably some back and forth.
DR.
BRAWLEY: Thank you. That helps a great deal. As time progressed, the sponsor did start
working on a trial which is now the SWOG trial.
The SWOG trial just began accrual in the middle of last year. The next question I have is there any
timeline or projected timeline for the accrual of what really is a large number
of patients, 900 patients. I know you
are going through a number of cooperative groups. It's a intergroup trial that extends into
Canada as well as the United States. Is
there a timeline that's estimated?
DR.
TEITELBAUM: They are estimating accrual
of 150 patients annually.
DR.
BRAWLEY: Six years of accrual.
DR.
TEITELBAUM: 2007 is when we are
anticipating according to their enrollment abilities and what they project.
DR.
BRAWLEY: That's more than 150 a
year. 900 total patients for 150
patients per year is six years of accrual.
Then watching survival.
DR.
HAMBURGER: In our response to the FDA,
we provided them with a timeline and it's estimated the accrual will be
completed in 2007 and we hope to have a supplemental NDA approximately 2009.
DR.
BRAWLEY: Okay. The first question I'm supposed to address is
has accrual to the on-going trial been satisfactory allowing for timely study
completion. My great concern and others
may want to speak to this is that the trial that is outlined shows what really
is very number of women every year who come into this situation.
It
would be nice if the accrual entry criteria could be brought and I'm admitting
I don't know how you could do that. Can
other members of the Committee help me with this? Is it reasonable to wait until 2009?
CHAIR
PRZEPIORKA: Dr. Carpenter.
DR.
CARPENTER: Exploring additional sites
particularly in Europe or some place where there are likely to be comparable
patients where there may or may not as many competing therapies might be a way
to get the number up. As I look around,
everybody I see is uncomfortable with the study that going to take six years to
complete accrual. If you were able to
cut that time perhaps in half then it might be a study which is much more
likely to succeed in its objectives.
CHAIR
PRZEPIORKA: Just a logistical question
to address that point. Because it's a
SWOG study and SWOG centers don't exist in Europe, if they tried to improve
accrual by opening another protocol in Europe and then did an analysis based on
the two protocols combined, would that be acceptable?
DR.
BRAWLEY: Yes, that's been done before.
DR.
PAZDUR: Yes. If it is prospectively done, we'd look at
this. It's not out of the question.
DR.
BRAWLEY: Yes, my greatest concern about
getting the answer in 2009 and finishing accrual in 2007 is it's rare the trial
that I see where accrual actually meets expectation. It's more likely that accrual to this trial
is going to be finished in 2010 and results available in 2012. It's also very likely that another drug is
going to come forth over the next five years and it's going to become even hard
to complete this clinical trial. That's
my advice for the day. Any comments from
the Committee?
CHAIR
PRZEPIORKA: Dr. Pelusi.
DR.
PELUSI: I would just again want to throw
out in terms of the difficulty of accruing people to clinical trials but I also
think we really need to look at some creative ways of working with the patient
advocacy groups to really have them understand how important it is to utilize
the clinical trials versus in community practice where it's already approved
for just going forward. They are a true
role in helping us make these determinations and what may be using them even
more in terms of getting the information out and on that effect, saying how
important these meetings are so that the consumer groups really begin to
understand the difficulty of getting some of these Phase IV studies done and
why their role is becoming more important.
CHAIR
PRZEPIORKA: And again just to address
the logistical issue that doesn't mean let the consumer groups go and find out
what they were and get all the information.
It means the sponsors being proactive, putting the packet together and
getting it over to the advocacy groups.
Ms. Mayer.
MS.
MAYER: I just want to suggest that there
may be times in which difficulty in trial accrual is essentially telling us
something we need to listen to about the efficacy of the drug in the current
environment and how that changes over time.
I don't know what role patient advocates will play in encouraging
enrollment to trials of a drug when there are better alternatives available in
the marketplace.
This
is one of the real problems with accelerated approval as a way of moving
forward. Unless withdrawal is enforced
in some way, it leaves drugs on the market for indications that have no real
proven efficacy. I don't know how we can
address that but I just want to put that out on the table.
CHAIR
PRZEPIORKA: Dr. Carpenter.
DR.
CARPENTER: I would submit that there's
not a better alternative out there than this study. The question is by 2007 whether it would
be. Right now, this study is probably
state-of-the-art. That's why efforts to
get the accrual up and get it done so the answers will become available at a
time when they are still pertinent to clinical practices what needs to be done
with this study.
DR.
BRAWLEY: Dr. Martino.
DR.
MARTINO: Just some practical
thoughts. I've been with SWOG for a long
time and I know how the intergroup tends to function. It often functions well within this country
and Canada where there are established relationships and mechanisms. We're not particularly good at establishing
mechanisms with Europe.
So
it probably would be futile to think that the intergroup in this country and
Canada could establish those relationships quickly enough to be of use for this
trial. If there are thoughts to expand
accrual, my personal advice would be I would ignore that pathway but rather
establish another group in Europe or elsewhere which then could be used as a
combination. That you probably can do
much more efficiently.
The
other possibilities could be the CTSU system which allows clinicians who are
not necessarily part of the intergroup mechanism access to these trials.
So there are some other pathways that are already established that can be
used to enhance accrual to these large trials.
DR.
TEITELBAUM: I just would like to say
that it is a CTSU study.
CHAIR
PRZEPIORKA: Thank you. Dr. Fleming.
DR.
FLEMING: Dr. Brawley and others have
been raising some very relevant issues about the SWOG trial and its feasibility
and timeliness. I'd like to step back
though and just revisit how we got to that trial and focus on the
interpretation of 30-49. But before
doing that, one quick question. There's
another trial 30-57 which is a randomized comparative study involving 214
looking at DOXIL versus Paclitaxel. We
didn't hear about it but our briefing documents refer to it. If I'm interpreting it correctly, it showed a
trend toward about 11 week longer survival on Paclitaxel than DOXIL.
DR.
TEITELBAUM: This study was started in
1997 and planned to enroll 438 patients in order to obtain the 350 valuable
patients. It enrolled a total of 214
patients from 33 sites throughout Europe.
It was discontinued early because Paclitaxel had become approved as
first line treatment in Europe.
When
the study was started, it was DOXIL versus Paclitaxel in patients with relapsed
ovarian cancer. The availability of the
Paclitaxel in Europe made it virtually impossible to enroll any additional
patients once the Paclitaxel was approved.
DR.
FLEMING: Do you have a slide on the
results? If not, I can just quote what
was in the briefing document.
DR.
TEITELBAUM: No, I do not.
DR.
FLEMING: Basically it looks as though
the response rates were four or five percent lower on DOXIL and median survival
was 45.7 on DOXIL and 56.1 on Paclitaxel which I'm sure doesn't prove
differences but suggests somewhat longer survival on Paclitaxel. The other data of course is the 30-49.
Just
to follow up on Stephen George's comments which I agree with, the prudence of
targeting follow-up in any trial until 90 percent of the events occurred is
very questionable. I would argue in
designing studies that if the median survival is three to five months, then I'm
comfortable with the 90 percent truncation point. But when it's up around a year, it's much
wiser to enroll larger numbers so that you are only having to follow until 75 to
80 percent of the events occurred.
That's what we're running up to against in this trial.
More
to the critical point though, what was the intention of 30-49? I can see a definite maturation in the
process between FDA and sponsors in how this accelerated approval process is
being implemented between the early 1990s and now 1999. The letter here is much more explicit about
what the expectations are.
For
this study, it is very explicit. The
likely evidence required to satisfy the Phase IV requirement would be to
demonstrate superiority of DOXIL over Topotecan in either time to progression
or survival with a supporting trend demonstrated for the other endpoint. That seems like a very rational criteria to
put forward.
What
I understand from the data that's been presented to us is numerically there is
no difference in time to progression and numerically there is no difference in
survival. So I'm perplexed. What was clearly laid out as a criterion for
what would be an adequate basis for approval was not only not met because we
had positive trends that weren't significant but the differences were trivial
between these two arms.
Now
there were subset analyses and we now get into and will be confronting later
also in these two days how to interpret subgroup analyses. The subgroup analyses are interesting though
at least this updated analysis that we're seeing here doesn't show a difference
in progression, i.e. it doesn't show an interaction of platinum-sensitive for
progression.
It
does show an interaction for survival which is an interesting issue. Is this real or is this as most of us would
anticipate in subgroup analyses more likely spurious due to excess differences
that you see when you look in a lot of subgroup analyses? How is it that it would be likely that a two
week difference in progression would translate into a 27 week difference in
survival? This is what we might call a
qualitative interaction because if you believe that there's a benefit in
platinum-sensitive then you have to believe that there's an adverse trend in
platinum-refractory.
There
is an interesting hypothesis being generated here. In fact, this is what we're now coming to Dr.
Brawley's question as to how do we confirm this. We're confirming it with a study that's going
to take six more years. Is this in fact
the logical conclusion of now extending what has been a four year accelerated
approval process here an additional at least six years unless we somehow can
rapidly enhance the accrual rate when the target that was clearly specified in
Dr. Temple's original letter was clearly not achieved in the primary analyses
of that study and you have a 30-57 trial which is at least suggestive that
there are better trends on survival of Paciltaxel?
DR.
WILLIAMS: Tom, I was originator of the
text that ended up in the letter. So I
know that our intent was to note that there was a trial nearing completion
which was not adequate to detect clinical benefit if it was there only if it
appeared as Topotecan. Therefore we
explicitly were not going to hold them
to a negative study. That was our
intent.
That's
probably the only accelerated approval letter I've seen like that where we had
an almost complete study and if they had shown superiority that would have been
sufficient. If they did not show
superiority, it would not be sufficient.
We said we would therefore ask for this other trial.
So
it doesn't meet the requirement perhaps that you're thinking that we would have
a Phase IV trial. It's a
commitment. If you failed that Phase IV
trial, therefore we will take your drug off the market. That was clearly not what we intended at that
time.
DR.
FLEMING: So just for clarification, at
the time of this letter in June 1999, you were laying out criteria which if
satisfied would lead to a full approval.
If not satisfied, what explicitly was your intention?
DR.
WILLIAMS: Wasn't that the next paragraph
that says therefore if it is not met, we will expect you to meet with us and to
plan a trial, etc.? That was in the next
paragraph.
DR.
FLEMING: Specifically you didn't have a
specific expectation of what that would be and it wasn't the 30-57 trial I
assume.
DR.
WILLIAMS: It was a trial to demonstrate
clinical benefit. It was a trial that
would probably be an add-on design. If
it didn't work, you might make the assumption that the drug didn't work. So that was our thoughts at the time.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: Grant, did they get caught up in
our growing insight into non-inferiority trials? There was a time within my memory when if you
showed that you ruled out the 20 percent loss and a hazard ratio that's 0.8, we
said that was good enough. We came to
realize that lots of times the control agent didn't have a 20 percent effect so
you weren't ruling out anything at all.
You weren't sure you were obtaining anything. A lot of attempts at non-inferiority got
caught up in this growth of insight. Of
course just to state the obvious, failure to beat the control agent doesn't
mean it doesn't work. It just means it
might not have been the best study design so that's why an alternative was
proposed.
DR.
WILLIAMS: I remember looking back but I
don't recall directly if there was an agreement that this would be sufficient
or not. You are correct that we have
become much more attentive to the effect size proven in trials and the
design. But at the time the trial was
designed, it was not designed to be part of the confirmatory trial for
accelerated approval. It's one of the
trials that comes in from the company as a Phase III trial. Then at the time of approval, we explicitly
recognize the deficiencies of the study and said that we would expect the
results soon and only if superiority would be satisfactory.
DR.
FLEMING: Just to follow up on Bob's
point, what's the lower limit of the confidence interval for the hazard ratio
for survival? If you took a more lenient
approach and said 0.8, does anybody know the answer to that?
DR.
MOHANTY: The lower limit was 0.775.
DR.
TEMPLE: But we didn't know what the
control agent's effect was in any credible way.
CHAIR
PRZEPIORKA: Dr. Taylor.
DR.
TAYLOR: We should go back to our patient
representative's comment. It's a good
point in terms of trying to complete these trials. It's a very common perception in our society
by both physicians and patients that new is better and that the older the trial
becomes the more difficult it is to accrue to and that if it's a new drug it
has to be better. Trying to be part of
the control arm is not something that patients necessarily perceive as
better. They may want even a Phase II
trial over doing something like this.
CHAIR
PRZEPIORKA: Dr. Brawley, did you have
more comments?
DR.
BRAWLEY: Yes, in keeping with Dr.
Taylor's comment, let's remember that this drug on clinical trial is competing
against itself in the open market. So an
individual who chooses to take Carboplatin alone or chooses to go into a trial
that would randomize the Carboplatin alone versus Carboplatin and DOXIL could
easily get Carboplatin and DOXIL off-study.
Unfortunately many people do tend to think that more is better. Many women I suspect would opt for
Carboplatin with DOXIL as opposed to a 50 percent chance of Carboplatin alone.
Also
I'm very concerned about is it fair to patients to have trials that last so
long. If there's any way to shorten it,
we ought to. We've had some interesting
discussions of ways to do it. Broadening
entry criteria is something that I would really stress needs to be attempted. Going to Europe, Dr. Martino talked about
some of the problems with that which we've seen before.
One
of the three questions that I was supposed to address is has accrual to an
on-going trial been satisfactory and allowing for a timely study. I think that we've address that issue. Strategies that might be used in order to improve
accrual. We addressed that issue. We've also addressed the issue and concern
about changes in the marketplace that may make this current clinical trial even
harder to do.
I
will just conclude. I was asked to
clarify a statement that I made in our first session this morning. I do believe that there are certain diseases
where drugs like DOXIL would benefit from relatively large, long case series
going to 10 or 12 institutions and trying to get every patient will allow the
information as they get this drug to be collected into a database to look at
trends and look at the number of patients who are getting DOXIL with HAART for
Kaposi's or DOXIL alone or DOXIL having failed HAART. I don't believe ovarian cancer is one of them
but Kaposi's probably is one of those diseases.
It's a very non-controlled study just collecting case series. It actually may be something that may be
useful in figuring if some of these drugs actually do work in those Phase II
like case series. I'll conclude. Thank you very much.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: We cannot forget that some of
these decisions may be out of our control because since this is now a SWOG
study it will be managed by a data safety monitoring committee. If accrual is suboptimal, that committee will
have the authority to recommend to the chair of the group to shut it down. Unless it is accruing at a sufficient rate,
it will be closed earlier than 2008, 2009 or 2010.
CHAIR
PRZEPIORKA: The summary that I've
collected from the comments today were to collect the treatment of patients
post-relapse to make sure that if there is a crossover you have something to
think about as to what happens with survival, work with the advocacy groups to
get the information out regarding where the study is being done and why it's so
important and consider a parallel protocol in Europe in order to accelerate
accrual and get this study completed as quickly as possible. Any other comments from the Committee? Mr. Fleming.
DR.
FLEMING: Just to the first comment you
gave about collecting, you are talking about the SWOG trial collecting data on
crossover.
CHAIR
PRZEPIORKA: Right.
DR.
FLEMING: I guess my own perspective on
that is that question that's being asked is a very relevant one if we believe
the subgroup analysis is at least as sufficiently reliable to generate a
hypothesis worthy of validation.
Actually that is a reasonable interpretation. If that's your perspective, then it's
answering a very relevant question. Can
we improve survival by adding DOXIL to Carboplatin?
DOXIL
at this point is not an established agent establishing effect in this
setting. So ideally what I would
encourage is that people if they are going to join the study sign an informed
consent where they would realize that there is substantial uncertainty at least
for them and their caregiver as to whether DOXIL is effective for them in this
particular setting when they're going to get Carboplatin.
If
so, then I would hope that those people who are randomized to the control arm
in fact wouldn't take DOXIL unless you believe the question of interest is
immediate versus delay. That's a much
more diluted question. Ultimately as a
statistician we're not going to be able to go back and adjust out the fact that
there are cross-ins on that control arm because if you censor them it's
informative censoring.
The
proper approach here is to say if you think you want DOXIL, then take
DOXIL. You can get it. It's available from accelerated
approval. If you are substantially
uncertain in this setting whether it will provide benefit to you, then we have
a trial that we would be interested in having you consider to be a part
of. In which case if you randomize to
the non-DOXIL arm, my hope is that most of those patients would use other
supportive care approaches. If they take
DOXIL, then you're presuming the answer that you already know it's a necessary
component. Now you are only answering
the question immediate versus delay.
CHAIR
PRZEPIORKA: Dr. Brawley.
DR.
BRAWLEY: Unfortunately, Dr. Fleming, it
ain't that easy. Those of us who talk to
patients and enroll patients in clinical trials our collected experience is
that more patients are going to say more is better and DOXIL plus Carboplatin is
more than Carboplatin alone. Therefore,
I don't want a 50 percent chance that some computer is going to give me
Carboplatin alone. I want both drugs.
Never
mind, the fact that you and I can both name a number of instances where the
added drug or added procedure has turned out to be the wrong thing. You saw some less than objective behavior
earlier today.
DR.
FLEMING: This gets right to the crux of
the issue about accelerated approval and the practical implications of an
accelerated approval. The control arm
here, Carboplatin, isn't only Carboplatin.
It's Carboplatin followed by best possible management of available
therapies which I would argue that if we're trying to establish whether DOXIL
should in fact be in that armamentarium then it shouldn't be one of those
"available therapies."
If
it's available from accelerated approval, I understand your point. It's now out there and the ability to
ultimately establish whether or not the addition of DOXIL to standard of care
whether that improves an outcome such as survival will now be forever
compromised because people will have the option if they choose to get access.
CHAIR
PRZEPIORKA: Dr. Carpenter.
DR.
CARPENTER: It's just unrealistic to
believe that this study is going to proceed any other way in the United States
except for the people who got Carboplatin alone which preceded Doxil or
relapse. It's probably one of the most
attractive third line drug that will be in this setting. It's completely unrealistic to think that
it's going to happen any other way. So
any consideration of a study design which doesn't take that into account is
just not living in this world.
CHAIR
PRZEPIORKA: So basically what we are
hearing is that survival may not be your best endpoint. If you are looking at clinical benefit, the
best you could hope for is time to disease progression. Dr. Redman.
DR.
FLEMING: What I'm hearing at least is
that all that's practical and what some people are saying is a strategy of
immediate versus delay. Ultimately if
delay provides part of the benefit what I'm hearing is we'll never know whether
immediate versus not use is in fact going to show a difference.
DR.
REDMAN: Just out of curiosity because I
agree that the DSMB is probably going to recommend that the study be closed
because it's not accruing, where do you go from that point?
DR.
GEORGE: I think we'll come back here.
DR.
PAZDUR: Back to the drawing board. But here again if you remember my comments,
part of this whole process is basically that we'd like several options and
plans for failure. Not every clinical
trial is going to meet its objective and methodological problems will intervene
and crossover will intervene. What are
other plans? Here again we're looking
forward of using this experience for other drugs.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: We will be back for more
discussion of time to progression. I
just need to mention that studies are typically sized for the time to
progression and you hope that you get overall survival. If the benefit is the same two months, then a
hazard ratio of 0.8 for time to progression becomes a hazard ratio of 0.9 even
if you retain it all when you double the time.
You start to get into trial sizes that are very different from what we
now do. But we want to discuss all of
that. I just want to put an advert in
for the add-on study which at least has a chance.
CHAIR
PRZEPIORKA: Mr. Ohye.
MR.
OHYE: I'm going to defer my
comments. Thank you.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: I was going to say that clearly
we should rediscuss the issue of time to progression. We have a recent colon cancer trial in which
this issue came up. This is not the time
I guess but sooner or later we should spend considerable time on that.
DR.
PAZDUR: Just to give a plug. As you all know, we are in discussions with
ASCO to start looking at specific diseases and endpoints. We're planning
the first meeting on lung cancer to look specifically at endpoints which will
be held in April. We plan on going on to
other meetings.
Obviously
these meetings with ASCO are not advice-giving meetings. They are meant basically for a
discussion. The only people we could
take advice from are you all so we will be coming back with the ASCO
discussions to you on specific diseases.
We plan on doing this over the next couple of years.
CHAIR
PRZEPIORKA: May I ask? Will the members of this Committee be invited
the discussions at ASCO?
DR.
PAZDUR: There are members that have been
either past or present. I believe past
members have. One of the reasons why we
wanted to have it separate is that there is a separate discussion and we
included basically people that had specific disease interest in a disease.
CHAIR
PRZEPIORKA: In that case, will
individuals participating in the ASCO discussion come here at a future time?
DR.
PAZDUR: Yes, we plan on having this as a
discussion where they would come with us to discuss these endpoints.
DR.
WILLIAMS: The meetings will be open too
so you can come.
CHAIR
PRZEPIORKA: Any other comments or
questions for Drs. Williams or Dr. Hamburger regarding this protocol? Thank you.
In that case, the morning session is over and it is now noon. We will return at 1:00 p.m. for the afternoon
session. Thank you. Off the
record.
(Whereupon,
at 12:04 p.m., the above-
entitled matter recessed to reconvene at 1:08
p.m. the same day.)
A-F-T-E-R-N-O-O-N
S-E-S-S-I-O-N
1:08
p.m.
CHAIR
PRZEPIORKA: On the record. Thank you for joining us this afternoon. The first item on the agenda for this meeting
will be the open public hearing. The
speaker that we have for the afternoon session is Maryann Napoli from the
Center for Medical Consumers. Ms.
Napoli.
MS.
NAPOLI: For the record, I'm Maryann
Napoli from the Center for Medical Consumers in New York. We're a not-for-profit advocacy organization
that's never had any pharmaceutical funding.
Because our Center was founded to promote informed decision making, I
spent a lot of time listening to cancer patients and helping them make cancer
treatment decisions.
In
25 of the 27 years of our Center's existence, we've had a medical library
that's open to the public. The people we
attract are the kind of people who weigh and consider the evidence before going
on a drug regimen. In the years that
I've spent listening to people, I've been struck by the disconnect between what
oncologists say to people and what the patients hear. Oncologists when asked about efficacy
frequently answer in terms of response rate but what the patient inevitably
hears is survival rate.
I
think that most people with cancer would be shocked to know how unreliable
tumor shrinkage is as an endpoint and that it was the basis for accelerated
approval in 10 out of 11 cancer drugs and the sole basis for 10 out of 55 given
regular approval between 1990 and 2001.
Consider what most cancer patients want from a drug, significantly
prolonged survival and side effects that are too horrendous.
I
applaud the trend towards making clinical benefit a required endpoint. I hope that this committee will continue to
rethink and strengthen the accelerated approval process because it allows
expensive minimally-tested drugs on the market to enjoy a long period of
unearned hope and acceptance, drugs that have never compared to the standard
drugs.
No
matter what you decide to do as a committee, however, cancer patients must have
a way of understanding the basis for drug approval be it accelerated or
regular. I've looked at the label for
each of the drugs to be discussed today and concluded that the average
intelligent consumer could easily miss their accelerated approval status when
reading the Physician's Desk Reference which is the most popular book in
our medical library.
Sure
you can read the label and find mention of Phase II trials and partial and
complete responses. But what does that
mean to consumers? Yet people can go to
the FDA website where they'll see a list of drugs given accelerated approval,
but the explanation of accelerated approval is not readily understandable. Nor does it explain tumor response and how
debatable it is as a good surrogate for prolonged survival or even symptom
improvement.
Most
manufacturers of drugs given accelerated approval have not completed the
required confirmatory trials but you would be hard pressed to know that unless
you read the "Wall Street Journal."
The FDA website lists each drug's data of accelerated approval but not
the status of those required confirmatory trials.
We
advocates who write and translate and assimilate information for people with
cancer need to know this information. We
need to know how that due diligence is working out. We need to know whether companies are
compiling with the regulation and how long it takes them to do so.
All
cancer drugs should come with written information that's understandable to
consumers who need a summary of the supporting evidence. In fact, there should be something like a
black box warning to alert the consumer of a drug's accelerated approval
status. I thank you all for your
attention.
CHAIR
PRZEPIORKA: Thank you, Ms. Napoli, for
your excellent comments. Any questions
from the committee? None. Thank you.
Next is the Conflict of Interest statement by Ms. Clifford.
SECRETARY
CLIFFORD: The following announcement
addresses the conflict of interest issues with respect to this portion of the
meeting and is made a part of the record to preclude even the appearance of a
conflict. To determine if any conflict
exists, the Agency has reviewed the submitted agenda for this meeting and all
relevant financial interests reported by the Committee participants.
The
Conflict of Interest statute prohibits special Government employees from
participating in matters that could affect their personal and imputed
interests. However the Agency may grant
a waiver if the need for the individual service outweighs the conflict created
by the financial interest.
Accordingly
waivers have been granted to following individuals: Dr. Douglas Blayney for owning stock in two
competitors, each is valued from $25,001 to $50,000; and Dr. Scott Lippman for
serving on a competitor's speaker's bureau for which he has received less than
$10,001. A copy of these waiver
statements may be obtained by submitting a written request to the Agency's
Freedom of Information Office, Room 12A-30 Parklawn Building.
In
addition, we would like to note that George Ohye, the Acting Industry
Representative, owns stock in the sponsor and in three competitors. He receives retirement pay from the
competitor. His wife works for the same
competitor. Within the past year, he
consulted for the firm.
In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participant should exclude himself or herself from such involvement and the
exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose any
current or previous financial involvement with any firm whose products they may
wish to comment upon.
I
would also like to make an announcement on behalf of Katherine McComas. She was the woman who stood up in the open
public hearing earlier. She did leave a
survey and a box will be at the desk in the lobby.
CHAIR
PRZEPIORKA: Thank you. On to our first presentation then, Dr. James
L'Italien and Dr. Gordon Bray from Ligand Pharmaceuticals to discuss the Phase
IV commitments on BLA 97-1325, ONTAK, for treatment of persistent or recurrent
cutaneous T-cell lymphoma in patients whose malignant cells express a CD25
component of the IL2 receptor.
We
actually have a second person who wanted to make an additional comment, Ms.
Mary Pendergast, if you can come to the podium to talk about FDAMA. I would ask that you provide your conflict of
interest information prior to your comments.
Thank you.
MS.
PENDERGAST: Thank you. I would like to thank the chair for giving me
the permission to speak very briefly. My
name is Mary Pendergast. I work for Elan
Pharmaceuticals, a bio-pharmaceutical company.
While we don't have a dog in this particular fight that is to say one of
your drugs is not being considered by this committee, I think you should assume
that I have a conflict since I work for a company that may in the future seek
to get accelerated approval for one of our products.
The
reason why I'm talking here today is because I was formerly the Deputy
Commissioner of the Food and Drug Administration and before that a lawyer in
the office of the General Counsel at FDA for approximately 20 years all
together. I participated in the drafting
of the accelerated approval regulations and I'm very familiar with something
that hasn't been brought forward to the committee's attention yet in either the
FDA's documents or in the discussion today which is a law that was passed in
1997 called "The Food and Drug Administration Modernization
Act." That law was based in large
measure on the activity the FDA had taken to speed drugs to the market through
accelerated approval.
But
it gave the agency additional authority, additional discretion to deal with the
kinds of circumstances that the committee is being asked to face today. In particular, the Food and Drug
Administration Modernization Act gave the agency the authority to waive the
requirement for the Phase IV confirmatory trials and it gave the agency a
discretion to decide to not withdraw the drugs should those trials be not
completed or negative.
Let
me just read to you from the law. As the
law was passed in 1997, these kind of accelerated approval products are called
"fast track drugs." Congress
had told the agency that they should speed the development and approval of
"fast track drugs." So Section
506(b)(2) of the Federal Food, Drug and Cosmetic Act which was added by
Congress in 1997 states
"Limitation:
Approval of a fast track product under this subsection may be subject to the
requirements."
Then
"Requirement A: That the sponsor conduct appropriate post-approval studies
to validate the surrogate endpoint or otherwise confirm the effect on the
clinical endpoint." Congress used
the word "may." The agency is
not compelled to require those Phase IV trials.
As Dr. Pazdur said I think mistakenly, the Phase IV trials are not
mandatory. The FDA can choose not to
require them. However should the agency
choose to require them, then of course the company must do them. It says that it's definitely mandatory from
the company's perspective.
Similarly
the FDAMA provisions give the agency the ability to withdraw expeditiously an
NDA if the sponsor fails to conduct the required post-approval study. But it does not demand that the agency pull
the drug from the market. The law
reads: "The Secretary may withdraw
approval if: (a) the sponsor fails to conduct any required post-approval study
of the fast track drug with due diligence..." Then there are subsections (b) and (c) that
deal with what if they do the study but the study is negative.
I
bring this to your attention because in particular Dr. Fleming seemed to be
under the mistaken impression that it was essential that all these Phase IV
trials be done and that it was required that the agency pull the drugs from the
market should the trials not get done or if the trials are negative. The law is quite clear that it's not the
case. Thank you.
CHAIR
PRZEPIORKA: Thank you very much. Are there any questions?
DR.
CHESON: A point of clarification on the
conflict of interest. I believe that
Elan Pharmaceuticals does have a relationship with Ligand Pharmaceuticals. At least in Europe, they are co-developing
several of the products such as the one that I'm discussing.
MS.
PENDERGAST: Thank you and I know we used
to have a relationship with Ligand but we got out of it. Like I said, consider me conflicted.
CHAIR
PRZEPIORKA: Thank you. Other comments? Excellent additional information and
clarification. Now on to Dr. L'Italien
and Dr. Bray.
DR.
L'ITALIEN: I'd like to begin this
afternoon by thanking both the committee and the agency for the opportunity to
present some of our recent advances in our Phase IV commitments for ONTAK. We'd like to actually divide the presentation
today. Dr. Gordon Bray is going to be
giving the presentation.
Let
me also begin by saying I'm the Senior Vice President of Regulatory Affairs for
Ligand Pharmaceuticals. Dr. Gordon Bray
is our Senior Medical Director of Clinical Research. Dr. Andres Negro-Vilar is our Senior Vice
President of R&D and Chief Scientific Officer is here to respond to
questions as is Dr. Eric Groves, Vice President of Project Management and Dr.
Francine Foss, Professor of Medicine at Tufts-New England Medical Center, who
is acting as a consultant for us in our discussions today. Let me introduce Dr. Bray.
DR.
BRAY: In the next 15 minutes I would
like to review the structure mechanism of action and clinical characteristics
of denileukin diftitox or as it's currently known by its proprietary name,
ONTAK. I'll review the clinical basis
for accelerated approval of this product and some of the key milestones that
have taken place in conjunction with its development.
I'll
describe the outstanding clinical commitment upon which final approval is
contingent and specifically I'll speak to the progress that we've made to date
in completion of that commitment, some of the on-going efforts that we have
undertaken to that end. In keeping with
the request of the FDA, we are going to also discuss some of the challenges
that we've encountered in our efforts to complete this outstanding clinical
commitment. At the end of all this, I
will sum up.
To
begin with, ONTAK is a recombinant fusion protein that consists of the
catalytic and membrane translocation domains of diphtheria toxin fused to the
full length amino acid sequence for IL2.
It's a protein that's designed the cytocidal activity of diphtheria
toxin to tumor cells that express the receptor for IL2. Leukemic and lymphoma cells of both B and T
cell origin including cutaneous T-cell lymphoma for which this product is
primarily indicated constitutively express one or more subunits of IL2 receptor
on their cell surface.
This
slide describes in a simplistic fashion the mechanism of action of ONTAK. It's helpful to begin briefly just by
reviewing the structure of the IL2 receptor.
As most of the members of the committee are no doubt aware, the IL2
receptor exists in a series of isoforms that vary with respect the
representation of individual polypeptide subunits.
On
the upper left-hand corner of the slide you will see a cartoon representation
of High affinity IL2 receptor which consists of the alpha subunit or CD25, the
beta subunit CD122 and the gamma subunit CD132.
The intermediate affinity receptor for IL2 consists solely of the beta
and the gamma subunits. Upon binding to
either the intermediate or high affinity receptor for IL2, ONTAK will mediate
signal transduction and internalization of the complex viracept mediated endocytosis.
Within
the acidic environment of the endosome, a series of furin mediated proteolytic
cleavages take place that result in the liberation of the catalytic moi doi
diphtheria toxin and its liberation into the cytosolic compartment. Within the cytosol, the catalytic moi
doi diphtheria toxin potently inhibits
protein synthesis by ADP ribosylating elongation factor 2 which ultimately
results in the death of a cell by apoptosis.
ONTAK
is indicated for the treatment of patients with persistent or recurrent CD25
positive cutaneous T-cell lymphoma or CTCL.
It has been shown to have an acceptable safety profile. Its use is associated with minimal
myelosuppression.
Accelerated
approval for ONTAK was based on data in CTCL patients from two clinical
studies. In a Phase I/Phase II dose
escalation study, 37 percent of the patients demonstrated at least a 50 percent
reduction in their overall tumor burden.
In a Phase III dose comparison study, the overall rate of response which
was the primary efficacy endpoint was 30 percent. Full approval of ONTAK requires completion of
a three arm, blinded, placebo-controlled trial in CTCL which is know as
L4389-11.
I'm
pleased to report that L4389-11 is on target for submission of a final study
report in early 2006 consistent with prior communications with the agency
involving the status of the trial.
Now
this slide lists some of the key milestones that have taken place in
conjunction with the development of ONTAK.
In August 1996, the product received orphan drug designation by the
Office of Orphan Products Development.
In December 1997, a biologics license application was submitted to FDA
by Seragen, Inc. In February 1999, the
product received accelerated approval under Subpart 8 at which time Ligand
Pharmaceuticals assumed all development responsibility for ONTAK from Seragen.
The
next couple of slides I'd like to get into some of the specific designs
elements for the L4389-11 study.
Patients who are eligible for this study must have persistent or
refractory CTCL and they must have disease stages between stage I(a) and
stage III. Importantly all patients must have tumors
that express CD25 on the surface of their tumor cells. The reason that this is an important point is
because only about 60 percent of patients with CTCL have CD25 positive
disease. Similarly all patients must
have had fewer than or equal to three prior therapies at the time that they
present for enrollment in 4389-11. The
primary efficacy endpoint of this study is the objective rate of response and
the two secondary efficacy endpoints are time to progression and response
duration.
Following
discussions and correspondence with the agency that occurred during much of
1999, the study population for L4389-11 was increased from 120 subjects who
were to have been randomized in equal numbers into the placebo arm of the study
as well as into the two active treatment arms of the study to 195 study subjects
which in essence would result in a randomization ratio of one placebo patient
for every two patients in each of the active treatment arms of the study. This modification in the study population was
felt to maintain the original size of the placebo group but it weighted
randomization towards active study drug in an effort to encourage enrollment
into the study post approval.
Patients
who present for enrollment in the study are screened for eligibility and CD25
status of their CTCL. Those who meet all
eligibility criteria are randomized to receive up to eight courses of either
placebo, 9 or 18 ug/kg/day of ONTAK on five consecutive days every 21
days. Tumor burden is assessed at
baseline and at day one of each cycle of therapy subsequent to cycle one.
I'd
like to talk a little bit about some of the progress that we've made since
endeavoring to complete enrollment in this study. Subsequent to assuming responsibility for
this clinical trial and adaptation of the 1999 amended protocol, enrollment in
the study has increased progressively through the first quarter of 2003 during
which time seven new study subjects have consented to participate in the trial.
Ligand
has made significant efforts to increase enrollment in the study by bringing
new study sites on line from various different geographies. What this slide shows is that in the year
2000 the number of study sites has increased from nine to 22 by the end of
2002. And by the end of the current
quarter, we will have 28 active study sites enrolling patients from North
America, Europe and Australia.
Just
to sum up the current status of the L4389-11 study, we've now enrolled a little
bit more than 50 percent of the total number of patients required to complete
the trial. There are 28 active enrolling
study sites in Europe, North America and Australia. There were seven patients who were
enrolled in the first two months of 2003
which is a source of some encouragement to us.
We estimate that approximately 29 of the 39 required placebo patients
have already been enrolled in the study.
We're on target for submission of a final study report for the trial in
early 2006.
The
agency has asked us to address some of the difficulties and challenges we've
encountered in getting us to where we are today. I've actually listed those on the next slide:
the small size of the patient population and the relative paucity of clinical
research centers that have a seminal interest in this disease; certain practice
patterns or standards of care for CTCL as they impact eligibility for the
study; impact of prior therapies on eligibility; and impact of the placebo
arm. These have each had effects on our
ability to recruit patients into this trial.
I'm
going to spend the rest of my presentation going to each one of these in
greater detail. To begin with, CTCL is
an uncommon disease. It constitutes only
a little bit more than two percent of all patients with lymphoma in the United
States. It has an annual incidence of
approximately four per million. So there
are only a little bit over 1,000 new U.S. cases of CTCL reported per year. We've estimated that only approximately 400
CTCL patients were treated with ONTAK in the year just concluded.
I'd
like to begin to get into some of the effects of practice patterns as they
related to eligibility for the trial and how that has affected enrollment. To begin with, it's important to consider
that most patients with CTCL are regarded as having rather early stage disease
or late stage disease. Early stage
disease encompasses Clinical Stage IA to IIA and these are patients who have
exclusively patch and plaque disease.
Late stage disease is patients with Clinical Stage IIB. These are patients with cutaneous tumors all
the way through and including Stage IVB which denotes extracutaneous visceral
involvement.
Now
it's clear that for early stage disease
the standard of care involves the use of topical therapies either
individually or in combination. I've
listed some of those here in the left lower portion of the slide: topical Nitrogen
mustard, BCNU, bexarotene gel, ultraviolet light, electron-beam therapy and
also extracorporeal photophoresis. These
are the therapies that are commonly used in patients with early stage CTCL.
It's
not until patients begin to become refractory to these therapies either
individually or in combination that the role of systemic therapies begins to
assume greater importance in the management of this disease. So patients who become refractory to these
topical therapies with early stage disease or patients who present with later
stage disease are much more likely to be treated with agents like oral
bexarotene, interferon, ONTAK, oral methrotrexate, combination chemotherapy and
purine analogues such as deoxycoformycin.
Now
as I indicated earlier, patients with Stage IV disease are ineligible for
L4389-11. And only patients with Stage I
to Stage III disease can enroll and only patients who are CD25 positive can
enroll. Taking all of these issues into
consideration, it's apparent that patients with early stage disease are not
going to be considered or have not been considered good candidates for this
study because these are patients for whom topical therapies are considered the
standard of care.
Contrary-wise,
patients who are refractory to these topical therapies or present with late
stage disease are often considered ineligible for the trial because by the time
they present for enrollment, they will have received more than the maximum
number of prior therapies required by the study.
We've
observed the impact of the placebo arm in a number of different context that
have involved patients, investigators and one example even opposition to the
study on the part of a governmental agency.
Patients will often decline participation in the study because they
often present with their primary disease and with recurrences with severe
pruritus or ulcerations which have a debilitating effect upon their quality of
life. Severe pruritus occurs in excess
of 75 percent of patients with this disease.
I
might add that systemic and/or topical steroids which are often used to manage
the pruritus in CTCL are exclusionary in terms of eligibility for this
trial. Also patients who have
ulcerations, the ulcerations frequently serve as a portal for systemic
infection which is a serious cause of morbidity and mortality in these
patients.
Investigators
are reluctant to consider a placebo control in this situation particularly
insofar as patients may remain on placebo for up to eight cycles or until
there's clearly demonstrable progressive disease. That's especially true for late stage
patients where spontaneous remissions in this disease have not been known to
occur.
Finally
efforts in the year 2000 to involve six study sites in France were rebuffed by
the Ministry of Health when a clinical trials application was submitted and
sought for in the conduct of the trial in that country. The French Ministry of Health declined the
clinical trial application citing the March 2000 revised Declaration of
Helsinki as the basis for declining the study.
So
in summary, Study L4389-11 has been enlarged from 120 to 195 patients in order
to encourage patient enrollment while maintaining the original size of the
placebo group. It is a multicenter,
international study that has been expanded to involve a total of 28 study sites
in Europe, North America and Australia.
We estimate that between 1.5 and 2 patients per site per year will
achieve the goal of completion by 2006.
Finally, I would just like to reiterate that we are on target for submission
of a final study report for this clinical trial in early 2006. I appreciate your attention.
CHAIR
PRZEPIORKA: Thank you, Dr. Bray. If you could keep your place at the podium
for discussion. I would like the new
members of the division who have joined us at the table to introduce themselves
please.
DR.
MILLS: George Mills, FDA.
DR.
SCHECHTER: Genevieve Schechter, FDA.
DR.
KEEGAN: Patricia Keegan, FDA.
DR.
WEISS: Karen Weiss, Center for Biologics
(CBER), FDA.
CHAIR
PRZEPIORKA: And Dr. Mills, do you have
any comments on the presentation or specific instructions for the committee.
DR.
MILLS: I defer my comments. Dr. Schechter or Dr. Keegan, do you want to
go forth?
DR.
KEEGAN: Our comments are really limited
to the fact that this is a little different from some of the discussions this
morning in that the trial that was going to be the confirmatory trial was
underway prior to approval. What it
really ran into was a lot of stumbling blocks in terms of continuing to accrue
patients in that study. We see that as
really a major problem in terms of completing this and getting full approval for this product.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: Patricia, that does lead right
into at least what I see one of the key issues.
I don't think we saw this as a slide but in our briefing documents on
page 10, figure 3, it gives specific information on enrollment.
The
good news is we are halfway there in
total enrollment if in fact it's good news.
It took us three years to do so.
The other good news is we were underway before the accelerated
approval. The bad news is if I
understand this it looks like the enrollment over the last three years has been
nine, seven and nine respectively. There
is this recent accrual that has occurred in the last few months.
The
first issue is if the extrapolation of what we've seen in three years to the
future is a relevant extrapolation, it's not three years. It might be more like eight to ten years
before we would finish this. That's the main
issue but the second issue is it's been very apparent that this slow enrollment
has been in place for quite some time.
It would suggest to me that it's not an easy thing to fix or we would
have already fixed it.
DR.
KEEGAN: We've had two attempts to fix
it. There were so many patients already
accrued at the time that we were reviewing this for accelerated approval. So there was the perception that we had good
accrual rates that the sponsors themselves suspended the trial while we
discussed ways to modify it to actually increase the accrual rates. There was a period of time where the accrual
was suspended.
The
perception was that if there were fewer patients randomized to placebo that it
would fix the problem. Clearly that's
not occurred. So the sponsors now made
additional efforts to go outside the U.S. to seek additional sites. I'm not sure that we've had enough time under
that process to know if that will address the issue or not.
CHAIR
PRZEPIORKA: Dr. Redman.
DR.
REDMAN: Just out of curiosity, what was
the time period that those 70 some odd patients were accrued prior to the
approval?
DR.
L'ITALIEN: The time period was
approximately three to four years. It
was about 14 patients per year.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: This might apply to other trials
that are accruing slowly so first it's a question for information I don't
know. Is there a plausible biological
reason why three prior regimens for topical therapy - I assume that's a part of
a prior treatment - would in light of the knowledge that you have today if you
have any new knowledge bar patients from entering the study? In other words, is there a reason to think
that if they got UV or something else that it would make the drug that you are
testing work less well? If it would then
obviously that's the reason.
DR.
L'ITALIEN: Sure. Yes, I have Dr. Francine Foss who is an
expert in the treatment of CTCL here with us today. I would like to have her address this
question.
DR.
FOSS: That's a very important point and
that's in my opinion one of the major issues that's forestalled accrual in this
study. One of the issues is that when we
actually started this study we didn't have available two agents that we have
now that are in very common use in this patient population, mainly the topical
bexarotene gel as well as the oral bexarotene.
If
you look at the way this disease is managed primarily early on in the course of
the dermatologist's office, many of these patients get a succession of topical
therapies and then perhaps oral therapies.
Many of these patients don't even come to see the oncologist until
they've already had multiple topical therapies as well as oral Targretin and in
some cases oral methotrexate as well.
If
you look at all of the literature out there and you exclude the IA patients
which are the patients that present with less than 10 percent of their body
surface area involved with patch or plaque stage disease and if you look at
stage IB and above, historically that group of patients has not been a group of
patients that's been cured using any of these topical modalities.
If
you look back at some of the earlier literature where ostensibly there were
patients who were cured with topical therapies, in fact almost all of those
patients with topical nitrogen mustard and electron beam therapy had stage IA
disease. Because of the histopathologic
confirmation of the disease was not in place in those studies and certainly it
would be difficult to retrospectively go back and address that issue, in fact
many of those patients may not have had mycosis fungoids.
If
you look at studies that were done recently both at Stanford and at UCSF by Dr.
Zackheim and Dr. Kim, there are 35 to 40 retrospective analyses, case control
studies looking at patients with mycosis fungoids matched to normal population
based on age and sex. You can see that
patients who had stage IB or greater disease had a disease that impacted their
survival. In other words, they had
incurable disease. That's irrespective
of treatment. Again most of these
patients get multiple topical therapies before they move on to systemic.
In
terms of thinking about the impact of therapy on this disease once you are
stage IB, you have a disease that's going to impact your survival. You have a disease that's incurable. Most of these patients will go on and receive
multiple topical therapies before they even get to a systemic therapy.
In
fact if you look at the pivotal trial for ONTAK, the median number of therapies
was between five and six. Similarly for
the Targretin study as well. That's the
group of patients that going to present to us in the oncology community for
systemic therapy.
I
personally don't believe and I don't think there's anything in the literature
to suggest that topical therapy by itself is going to make any significant
impact on the disease. Nor is there any
suggestion that numbers of topical therapies versus a single topical therapy is
going to make an impact.
I
would strongly be in favor of basically not putting any limit on the number of
topical therapies that a patient could receive but focusing more on number of
systemic therapies if we want to select a group of patients that's earlier on
in the course of the disease that's not beaten up by having received two or three
courses of multi-agent chemotherapy.
DR.
L'ITALIEN: Thank you, Dr. Foss.
DR.
KELSEN: Can I follow up on that then?
CHAIR
PRZEPIORKA: Sure.
DR.
KELSEN: So my broader question which is
being addressed to the agency was that when there are trials that are slow
accruing in relatively small populations, there may be a point in which new
knowledge or re-appreciation of knowledge that was available before would allow
you to change eligibility criteria. It's
clearly a tricky issue because you don't want to change the rules in mid-game
too much. I'm struck by the fact that
we're seeing this now a third time today that we might approach the issue of
changing not crucial parts of a Phase IV study in order to get to the essence
of whatever we want to get. If it's
accrual that's a problem because of a technicality that's not as important as
we thought, we ought to address that.
DR.
L'ITALIEN: Right. One of the things that we need to consider
today is that we have made great strides recently in enrolling new sites. These sites are just starting to manifest
themselves by showing patients into the studies. The fact that we have seven patients in the
first two months of this year is already a reflection of the work we did in the
last year to bring new sites on board especially in Europe and we're adding
another six sites I believe this first quarter
We're
certainly open to consideration of the number of prior therapies as a means of
potentially increasing enrollment but we really first want to take a look and
see what actually may be happening with the current sites and their enrollment. Then from there, certainly consider this as
an option to discuss further with the agency.
CHAIR
PRZEPIORKA: I have a question. Although the majority of the patients will be
CD25 positive, is there any pre-clinical information to suggest that the CD122
positive patients should not also be participating in this study?
DR.
L'ITALIEN: We actually do have a
companion trial and perhaps, Dr. Bray, would you like to address this topic
specifically?
DR.
BRAY: All of the preapproval clinical
data that is the basis for the accelerated approval is based upon patients who
expressed CD25 on the surface of at least 20 percent of their tumor cells. This was determined by an immunohistochemical
assay. There was some earlier clinical
work looking at antibodies CD122 as the basis for determination of
eligibility. This is basically not
including the studies that I have discussed.
There
were a number of reasons why CD25 was chosen as the screening methodology. The antibodies were much more readily
available. There was a good assay
methodology in terms of evaluating patients for eligibility. That was one of the reasons why. Francine, do you have other insights?
DR.
FOSS: When we did the Phase I study, the
dose escalation study, we treated patients with Hodgkins, non-Hodgkins and
cutaneous T-cell lymphoma. In that
study, we did immunohistochemistry for both the alpha and beta components of
the receptor. At that point, we really
didn't have the antibody for the gamma chain.
When
we went back retrospectively and did a correlation between the expression of
the receptor isoform in clinical response, we really did not see a strong
correlation in that not all of the patients who expressed the High affinity
form of the receptor namely at that point, alpha/beta responded at about 40
percent. There were patients who
expressed only the beta component without alpha.
I
can specifically remember two out of a denominator of 12 of those patients
responded. Likewise, there were patients
who expressed CD25 without expression of the beta component who also responded
across the different histologies. That
suggests that immunohistochemistry at least the way were doing it at that time
for that study was not strongly predictive of who was going to respond.
Subsequent
to that in my laboratory, we are doing a retrospective analysis, a PCR-based
analysis, of those same specimens and all of the 73 CTCL patients that were treated on the pivotal trial. We're looking specifically to see if we can
correlate the expression of the receptor isoform with response. I can't give you the exact data yet because
we haven't done all the correlations but I can tell you that many of those skin
biopsies from the CTCL patients in fact do express the beta component of the
receptor.
I
don't the answer in terms of who is going to respond here is going to lie
solely in the expression of the receptor isoform. Hopefully in the future if we do microarrays
and other kinds of analyses, we may be able to predict better who is going to
respond and certainly there are other factors with respect to how we deliver
this drug. On the surface of it, we
really don't have any good data to suggest that immunohistochemistry by itself
is going to be a strong predictor of response.
DR.
L'ITALIEN: Thank you.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: Although you're adding these
additional sites, part of the problem is your old sites. You barely have a patient a year per site at
these other institutions. Some of the
sites you are projecting are in Russia and elsewhere. Do you have some idea of their track record
in (a) participating in clinical trials and (b) in CTCL trials?
DR.
L'ITALIEN: Yes, I'll ask Dr. Bray to address
that specific question.
DR.
BRAY: Yes, there are five study sites,
four in Moscow and one in St. Petersburg.
They're all large medical institutions referral facilities, most manned
by oncologists. At one of the centers
there's an academically oriented dermatologist who is the investigator. These are centers that have had a track
record for the conduct of multi-institutional clinical trials.
In
my view, they have been determined to be pretty medically sophisticated. I met with all of them individually. We have at this point in time a lot of
confidence that they will be able to enroll patients in the study. The perspective generally among investigators
outside of the United States has been that they are interested in the trial
because the product is not approved in their jurisdiction and it represents
another therapeutic option for their patients that they don't have access to.
DR.
CHESON: Which raises another issue. Since you are targeting mostly oncologists,
shouldn't you be targeting mostly dermatologists?
DR.
BRAY: That's an interesting
question. As Francine alluded to, the
disease is really cared for in the very early stages by community-based
dermatologists and some academically-based dermatologists. Some academically-based dermatologists that
have access to infusion facilities will often times administer systemic
therapies to these patients including ONTAK.
They virtually never administer cytotoxic chemotherapy. But therapies like interferon for example and
ONTAK have been and are used by academically-oriented dermatologists and by
clinical oncologists.
If
you look at the distribution of investigators in the study before 1999 and
after 1999, it's about a 50-50 split in terms of the number of dermatologists
and clinical oncologists who are represented in the clinical study group.
DR.
CHESON: Because if you could target and
at least educate the dermatology community about the trial, they perhaps
wouldn't be putting patients on three, four, five or six topical approaches
before they sent them and rendering them ineligible for the study.
DR.
BRAY: That's a really good point. There's one initiative that we've basically
embarked upon in Canada where one of our investigators is located. He has asked us if we could provide some
information about the study to a group of community-based dermatologists in his
catchment area which we are planning to do in the interest of essentially of
eventually trying to facilitate referrals.
When and as those kinds of opportunities do present themselves, we seize
upon them if we can.
DR.
CHESON: Of course, in essence we have
what appears to be an active drug here based on a 30 percent response rate in
two separate trials that's limping along for a number of fairly obvious
reasons. It's slowly getting there. I agree with my colleague's skepticism based
on the decreasing rate of accrual except for the recent period of time. If we could educate these sorts of population
early, then we could hopefully increase the accrual to what is an important study. Now going through the prospectus here on the
initial Phase III trial, could you review the differences between the two dose
levels, both toxicity and activity?
DR.
L'ITALIEN: Dr. Bray.
DR.
CHESON: Since a three arm trial with
trivial numbers of patients available is a real challenge anyhow.
DR.
BRAY: The Phase III dose comparison
study evaluated nine versus 18 ug/kg/day on five consecutive days very much
like the Phase IV post-approval commitment confirmatory trial. The overall rate of response for patients in
the 9 ug/kg arm was 23 percent. For the
18 ug/kg arm, it was 36 percent. There
was no statistically significant difference between those two treatment arms
but there was a trend towards significance in a subgroup analysis for patients
with advanced stage disease who received the higher dose. With patients with Stage IIB disease or
higher, the response rate was 38 percent for patients who got 18 ug/kg/day and
it was 10 percent for patients who got 8 ug/kg/day.
DR.
CHESON: And toxicity.
DR.
BRAY: Basically my memory tells me that
the toxicity was comparable for both arms of the study. There was really no apparent difference in
the incidence of Grade 3 or Grade 4 toxicities between the two study arms.
DR.
CHESON: Then why a three arm study if
the activities trending towards better even if not significant and the toxicity
appears to be no greater in which you'd already have the study pretty much done
with a two arm trial?
DR.
FOSS: I was actually involved in those
discussions and there was initially a concern with these earlier stage patients
that perhaps we wanted to expose them to less toxicity. There is a slight difference. There is slightly less toxicity at the nine
dose but it's not statistically significant and given the number of patients
treated on that Phase III trial was small.
There
was still a concern because there was no dose response relationship with this
drug. There was a certain again to try
to demonstrate in fact if there is no dose response relationship one could
certainly use less drug and to just confirm the fact that the toxicity is the
same in a larger group of patients.
There you might see less toxicity.
Those were the discussions that I could recall. Pat, do you have anything to add?
DR.
KEEGAN: One thing to remember is this
study started a fairly long time ago in 1993 or 1994. At that time, the impression was that there
wasn't much of a dose response relationship at the upper doses. It was trying to further explore whether that
was a real conclusion or were there differences that were important to know.
Since
I have the mike, I would just like to add another comment about the inclusion
criteria. We haven't had a lot of
discussion about modification of the inclusion criteria predominantly because
as the company has said, they wanted to see how opening additional sites would
enhance accrual. We open to loosening to
some extent the inclusion criteria but we have to be careful about how loose it
is because we still want to maintain a protocol that will accrue to a placebo
control trial. There's a limit as to how
far you can go.
We
feel the placebo group is very important for some reasons that came out during
the original review. One of the
toxicities of concern was infectious toxicities as a direct mechanism of attack
of normal CD25 expressing T-cells and whether there was some risk in terms of
infection that we would only be able to capture in a placebo control trial
because of the high background rate.
It's very important that we try and figure out a way to increase the
accrual rate while still preserving accrual into a trial that really ought to
be placebo controlled if we want to get an answer to that question.
DR.
L'ITALIEN: I would like to emphasize
further that of the 22 sites that we listed in 2002 approximately 10 or 12 of
those occurred in the second half of the year.
What we are seeing now within the last six to nine months is we've now
accumulated these seven patients which we've incrued in the first two months of
this year.
DR.
CHESON: For how many sites?
DR.
L'ITALIEN: That has been from the total
of 22 sites.
DR.
CHESON: How many patients from how many
sites? Seven sites.
DR.
L'ITALIEN: It's pretty much about
one per site.
DR.
BRAY: One patient was enrolled in
Melbourne, Australia. Two in the
U.K. Two in Germany. Two in Warsaw, Poland.
CHAIR
PRZEPIORKA: Dr. George.
DR.
GEORGE: I had a couple of things. One is something we haven't discussed up to
now and I would like to hear a little bit about it. The primary endpoint of objective response
rate in this particular disease seems to me to be somewhat difficult but maybe
you can tell me otherwise. Has the
definition and/or the determination or process for the determination of
response in any way changed from the accelerated approval time to the current
study? I'm particularly worried about
the PRs and things being thrown into the objective.
DR.
BRAY: The response criteria are
virtually identical in comparing the Phase III pivotal dose comparison study
and the Phase IV confirmatory trial.
Partial response requires at least a 50 percent reduction in overall
tumor burden. Clinical complete response
requires elimination of all clinical evidence of disease. Complete response basically equates with
elimination of all evidence of disease with a documented biopsy of no abnormal
cells. Those are the criteria that were
used that have been used virtually adulterated in the studies that have been
done pre and post approval.
DR.
GEORGE: And you have a mechanism for
verifying this.
DR.
BRAY: For patients who have more than 10
percent body surface area involvement, there is a weighted severity index tool
that is used that essentially weights the degree of disease severity for a
tumor patch and plaque disease. For
patients with less than 10 percent of body surface area involvement, we use
basically five measurable lesions as index lesions in order to assess
response. There's an independent data
endpoint review committee that evaluates all of the results in a blinded
fashion in order to confirm the validity of the responses.
DR.
GEORGE: One other thing I'd want to ask
about is a follow-up of Dr. Cheson's issue concerning the logic of what we're
doing here. Accelerated approval was
based on an observed objection response rate of around one-third of the
patients if you combine the two studies.
This design was apparently set up and there's a real question about
whether it should have been a three arm study because even the proposed
analysis isn't really looking at dose response.
It
has an interesting logic that you'd have to follow. It says first you do an overall test to see
if there's any difference amongst the treatment. Then you start doing these contrasts. In other words, you compare the 9 ug to the
placebo and you compare the 18. Then you compare 9 plus the 18 to the
placebo. It's left unstated what happens
hypothetically if you find the 9 is better than placebo and not the 18 but when
you combine them maybe they are or maybe they're not.
You
get into conundrums here and again this is retrospective but perhaps this would
have been better done as a two arm study.
I gather that the reason it's as small as it is in the design is because
it must have been based on assuming that the placebo response rate would
essentially be zero or very low.
DR.
BRAY: I know the answer. So the study is powered to didact a
difference in response rate of 10 percent in the placebo arm versus 30 percent
in best response rate in either of the active treatments.
DR.
GEORGE: And you really don't expect much
response in the placebo but as Pat brought out a key would be still you're
worried about toxicity. So there is the
safety issue. Just the way this flows,
the logic is a little fractured to me.
That's just a comment. I would
have preferred a two arm study and made it cleaner.
DR.
L'ITALIEN: I think we have to bear in
mind that this study was initiated in 1995.
There were certain objectives that were present when the study was
initially starting to look at whether we did have a minimum effective dose to
try to establish that which is why we had two arms. At the time of approval, we had 73 patients
who had already accrued into the study.
We felt that in spite of perhaps the flaws that you might have
highlighted it still was perhaps our best chance at getting a rapid
confirmatory trial. We need to bear this
in mind. We're looking at this now. It is often easy to go back and take a look
and observe the flaws in the previous design.
DR.
BRAY: One other important comment is
that when this trial was initiated the results of the Phase III pivotal study
were not known. In fact that Phase III
pivotal trial wasn't concluded until the latter part of 1997. This study was already well underway for a
two year period of time by the time in fact that the overall response rate of
30 percent in the placebo study was appreciated.
CHAIR
PRZEPIORKA: Mr. Ohye.
MR.
OHYE: Earlier we had a discussion of
good news/bad news. I would like to
emphasize that I find a lot of good news here.
We see that the sponsor is getting a lot of instructive information from
a hypocritical review. They have been
extremely diligent in terms of trying to fulfill the Phase IV commitment. The good news is that we have a drug for an
orphan product out there already and it's been accelerated approved I'd like to
point out under the rule that requires that adequate and well controlled
studies be conducted that provide a likely benefit of the clinical
benefit. I think I have that wrong but I
think you all know what I mean.
When
you are dealing with an orphan indication where you have probably less than 100
patients per month presented, they are doing their very best and they should be
commended for trying to ramp up this study that was started way back in 1995
and the study they inherited from a previous sponsor.
CHAIR
PRZEPIORKA: I have a question for Dr.
Foss. Has there been a problem accruing
patients to this protocol because of the placebo arm?
DR.
FOSS: Yes.
CHAIR
PRZEPIORKA: How would you address
getting rid of that placebo arm?
DR.
FOSS: I'm glad you asked that question
because this study was opened at my institution and I enrolled a significant
number of patients on it. But once ONTAK
was approved, it was very difficult to convince patients to go into this
study. One major issue even before ONTAK
was approved is that patients are required to stay on the placebo arm of this
study until they have a documented progression. So we have to be able to
document 25 percent or greater increase in their overall tumor burden.
At
the same time, many of the patients actually were clinically not better. In fact their disease was progressing as
marked by their systemic symptoms such as pruritus and other systemic
manifestations. Yet we had to continue
to treat this patients at the time obviously not knowing that they were on the
placebo arm but we could not take them off the study because they didn't meet
those criteria. To expect a patient to
stay on a placebo arm where they are not clearly obtaining benefit for eight
cycles is a lot to ask for these patients because again they are all
symptomatic when they come into the study or we wouldn't be treating them.
In
order to look at this issue critically in terms of why sites in the U.S. can't
get patients on this study or unwilling to reopen the study, the major issues
are the prior therapy as I mentioned before because everybody gets Targretin
now. The other issue is if we could do
something to change the placebo arm not to eliminate it but perhaps to allow
patients to roll off of the placebo arm if they have systematic worsening.
In
terms of thinking about documenting that, in the Phase III trial, we used a
pruritus score and a quality of life tool.
Perhaps if we used those same tools in this study, we could allow an
early exit for patients who clearly weren't improving.
CHAIR
PRZEPIORKA: Yes.
DR.
WEISS: I just also want to clarify with
the sponsor. Because you are looking at
having a question about using some kind of subjective outcomes, what are the
unblinding effects of the product? Will
people know and will that somehow influence perhaps the attempt to exit early
from one arm of the trial?
DR.
BRAY: I'm sorry. Could you please repeat your question because
I only heard part of it.
DR.
WEISS: It's just a question about the
unblinding types of effects from administration of ONTAK.
DR.
BRAY: When patients meet the definition
of progressive disease as defined by Dr. Foss or if they have stable disease
after eight cycles of study drug, then there is the option for the investigator
to request that we unblind the patient.
If the patient when unblinded is found to have been randomized to
placebo, they are then offered the option to enroll in a companion study that
is an open label study that offers treatment to these patients at the 18
ug/kg/dose level.
I
might also add that this study has as a secondary objective also an effort to
identify a point estimate of response for patients with CD25 negative
disease. It's basically an effort to
have a one-stop shop for patients so that patients will commit to the screening
process, undergo the biopsies knowing that if they have CD25 negative disease
they have the option of presenting in another study. I don't know if that answers your question.
DR.
WEISS: That's helpful but there's
another half. Basically we have a
placebo control trial but whether or not there are unblinding effects,
infusional reactions and other kinds of things for administration of the
product. There's a question on the table
about maybe people could withdraw early and that might help the acceptance of a
placebo arm in the trial.
DR.
BRAY: Now I understand. Many patients do experience infusion related
constitutional symptoms with this product.
It's important to emphasize that investigators cannot request that a
patient be unblinded until they meet the objective definition of progressive
disease. The reality is that there are
certain infusion related constitutional symptoms and some hypersensitivity
manifestations that might have the effect that you described.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: I'd just like to return again
to this issue of enrollment and where we are.
I'm not really second guessing the original formulation of the trial
that in fact looked like it was reasonably enrolling until such time as the
accelerated approval occurred and then I have no question that the existence of
placebo which was part of the trial before but no longer a requirement because
patients could not get access to the agent without joining the trial has
negatively influenced the enrollment.
I'm just trying to get a sense of whether there is the sense of urgency
here that I uniformly witness from industry sponsors when we're in a
preapproval mode.
We
had in the year 1999 the hold that was referred to. Interestingly it was a hold to try to look at
how we would increase enrollment rates.
It's not exactly clear why we had to have a hold for that. Nevertheless there was a hold. Then in the year 2000 when there were just
nine participants enrolled if this had been a premarketing study in my
experience, sponsors would have been with the sense of urgency all over doing
something immediately radical because at that level we would be 10 years away
from finishing the enrollment. Nothing
changed.
Then
the next year when we again saw that same level of enrollment, then we doubled
the number of sites although that was in the year 2000. We doubled the number of sites in 2001. But by 2002 we still hadn't increased the
enrollment. Now what we are hearing is
there have been further increases. There
is more representation from Europe. What
is the threshold here? What's the
target? What's the acceptable level?
We
heard that there were seven enrolled in the first quarter of this year. If we maintain that, we will barely be at a
level where we could finish this enrollment in another three plus years. What if we don't maintain it? What is the strategy here? What is the sense of urgency? What is an acceptable minimum to be achieved?
Then
part of this question leads me back to what Drs. Cheson and George were saying
earlier which brings us back to surely I would love to have information on the
dose levels against control in an ideal world.
If we stopped enrollment at this point to the nine dose level, we could
reduce by 36 the number that would have to be enrolled. We would still have important clues about
nine against placebo. We would obtain
information about the 18 against placebo in at least one year less and at the
current rate of enrollment maybe three years less. I keep coming back. Do we have a sense of urgency here that we
would have if this were premarketing and do we have what is a minimum threshold
here but we have to achieve to continue the process?
DR.
L'ITALIEN: I would start the response to
this question by saying unequivocally we do have a sense of urgency to try to
complete this trial. In the year 2000 as
was presented in the briefing document and as Dr. Bray mentioned in his
response, we did try to initiate six additional sites in France and had initial
encouragement because those received local IRB approval which was subsequently
reversed at the national agency level.
It's
worth noting here that this is something because we are trying to recruit high
quality sites that there is a significant investment in time in identifying and
recruiting sites. Typically it takes
about a year in advance for this to happen before you can actually bring a site
on-line.
If
you take a look at the attempts that were made in the year 2000 to bring on the
six additional French sites, those were denied.
We then sought to bring on additional sites. In the block diagram that we presented in the
briefing document, you will note that we talk about active sites. The key here is that while certain sites were
also being brought on-line in 2001, there were other sites that were actually
disengaging from the study because they were having a difficult time accruing
into it. As a result of that, actually
two U.S. sites dropped in that particular year.
In
the second half of 2002, we had made substantial progress in bringing new sites
on-line. Our expectation is and it was
alluded to by several other committee members throughout the course of
discussion today that you actually have to initiate the sites and we're going
into sites that are purported to have a high number of CTCL patients. We then have to look at our accrual rates and
then adjust. We'll add more sites if we
need to.
At
this point though, Dr. Fleming, it's worth noting that we can't really drop one
of the active treatment arms for ethical considerations. At the current time given the overall
randomization target of one to two to two, one being placebo, two being low
dose and two being high dose relative ratio, we're actually enrolling at a
ratio of about one placebo to seven active treatment. 3.5:3.5 is the actual ratio to come up with
the overall number.
Currently
a patient enrolling has a seven in eight chance of getting active and a one in
eight chance of getting placebo. This is
what has been approved by the local IRBs.
It is certainly our opinion it would be very difficult to go back now
and retrench and ask them to go to a one to four randomization. We just don't think they would find that to
be acceptable even in geographies where the drug is not available.
We
have certainly thought through a number of the points that you have
raised. We are making a very strong
effort to accrue new sites. The other thing that's happened from this introspection
about the study in the recent dialogue we've had with both the agency and
amongst ourselves is that there may be some opportunities that have been
discussed today to look at ways we could do further enrollment if our rates of
accrual do not meet our expectation for completion of the study as outlined.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: I wonder if this discussion
doesn't touch on the issue of a qualitative difference between a pivotal Phase III trial leading to
approval and a post-marketing study. As
I listen to this discussion, I'm struck that if this was a Phase III
presentation and you brought it to the committee and said we changed
eligibility requirements and the randomization design and added a number of
centers, we would be wondering why we were be asking to look at that.
This
is a Phase IV study. We touched on this
a little bit earlier. I wonder if it
doesn't apply to many Phase IV studies.
There's one central point you're trying to get. You want to show that some crucial factor was
true in your study that led to accelerated approval. Many of these other factors while desirable
are less important. Some of that doesn't
come out until the study is underway.
When
I was listening to the discussion this morning, we talked about holding the
Phase IV trial to the same standards as Phase III. I don't hear that this afternoon. I don't know how the agency feels about that
but it seems to me that it's reasonable to look at a Phase IV study in a bit of
a different way than looking at it as a pivotal Phase III trial leading to full
approval. But I understand that might be
a controversial point.
DR.
L'ITALIEN: As Drs. Foss and Bray have
pointed out, there has been a certain evolution in the standard of care. There have been new topical therapies
approved. Certainly at the time of the
original study design, this wasn't contemplated because those other products weren't available. What we've talked about in terms of a
redefinition of prior therapies is really an outcome of the evolution of
topical therapies and also how this product is being positioned today by
oncologists who are treating patients with ONTAK.
CHAIR
PRZEPIORKA: Dr. Pelusi.
DR.
PELUSI: With all respect and not
sounding like having a major ethical issue here, we're going to see a same
issue in terms of there are going to some countries that have already approved
certain other drugs that are going to be here in this country that other things
are available. When we begin to look at
that placebo arm and where we can really do the accrual for that arm or make it
more conductive for people joining, the question becomes is there any thoughts
in terms of the agency on looking at those placebo arms being definitely arms
done in other countries. Again trying to
be fair to everybody and looking at randomization but I think you can see where
I'm coming from. If this patient issues
continues to come up whether it's here or in France or perhaps they have that
and we don't, can that be built into a trial?
DR.
KEEGAN: Remember that the first 73
patients that were accrued on the study were accrued in the United States.
DR.
L'ITALIEN: Yes, they were.
DR.
KEEGAN: So it was not considered an
unreasonable approach. The patient
population was selected as those with symptomatic therapy might be a reasonable
group in which another treatment could be delayed so that we could evaluate
this with the opportunity to go on.
One
other issue that I might remind the committee of was at the time that we
brought this product to the ODAC for the original discussion of accelerated
approval and discussion of additional studies came up, they were aware of this
trial that was on-going. There were also
discussions of other trials that might
be undertaken in more advanced disease and specifically in comparison to
interferon or other products.
The
sponsor has not come in with those sorts of proposals but I would like to hear
some discussion if people believe that this trial is not going to be able to
accrue and too much modification of the trial will make it unusable for terms
of interpretation of the results of the trial.
We were concerned when we made the modification to the randomization
scheme and made it more unbalanced how that might affect looking at the
results. There's a little trepidation
there.
There
is a thought that maybe there may come a time when there is so modification to
the trial that it is no longer an adequate and well conducted trial. Could I hear some discussion from the
committee about starting afresh with a new trial?
DR.
CHESON: Clearly what they are doing to
increase accrual has to be the first step.
That's increasing the number of centers that can provide high quality
data hopefully and maybe targeting and educating the dermatology
community. If that doesn't work then
everybody needs to have another look at this study.
DR.
L'ITALIEN: Certainly our intent is move
forward with the current design. We are
taking that very seriously to move forward and try to enroll sites and to go
globally in the search for those sites to try to attract appropriate patients
so that we won't have any major modification of the current study design. That has to be our first approach. That's what we are pursuing vigorously.
CHAIR
PRZEPIORKA: Just to address your
question about whether or not you'll end up with an interpretable study at the
end. Because of the imbalance between
the numbers to the placebo arm and the active arms if we don't keep the
exclusion criteria over the vast majority of the arms, you're right. Unfortunately the way it would pan out if
change the inclusion criteria to include patients with more topical therapy or
patients who receive 25 negative, you're going to be put disfavor in the
treatment arms. Clearly if you still
ended up with a significant difference, this drug could look actually pretty
good rather than pretty bad. Dr.
Brawley.
DR.
BRAWLEY: I'm stepping back here and
thinking about what we heard this morning and what we heard this
afternoon. I'm not at all being critical
of Ligand's efforts or Johnson & Johnson's efforts to accrue patients. I may even be sounding a little bit like the
advocates here but I'm starting to worry about the ethics of the time it takes
to get these answers.
We just heard 10 to 12 years on this trial.
One
of the ethical issues that I often worry about is some poor patient going on to
a trial wasting his or her efforts in that trial trying to be a good patient in
the trial and then we learn absolutely nothing from it. That's an insult to the patient.
One
of the great problems here is that accelerated approval which was brought with
the idea of trying to get these drugs to patients earlier actually is competing
with the clinical trials that ultimately help us figure out if these drugs
actually do work. God help us if we
approve one of these drugs and then actually perhaps by going to Russia or
someplace else do the trial and do the trial well and find out that this drug
actually hurts people. We actually have
had drugs approved in the past that we ultimately found out had a net harm
versus a net benefit.
We
need to step back and look at this accelerated approval process. There is a point that was made earlier that
once a company can make money - and I'm
not criticizing Ligand or anybody else who's here - once the drug is available
in accelerated approval and as Ms. Napoli noted most patients and I note I
suspect most doctors don't realize the difference between accelerated approval
and routine approval. Once a company can
make money off of it talking about a conflict of interest, you can sell here or
you can put someone into a trial where you have to supply the drug. You talk about a conflict of interest. We need to look very cautious at this.
DR.
CHESON: Another problem with the system
which should have been blatantly apparent to those who created it is the system
itself can kill the drugs. You can have
a drug approved by this mechanism, the accelerated approval, and because
everybody is so happy to get it out there, no one goes on the clinical trials,
the trials don't get done and therefore the drug gets yanked from the market
even though it was an active drug because it was approved as some of them have
been on some very skimpy data. At some
point, the agency really needs to look at this accelerated approval and see if
it has the potential to do more harm than good.
CHAIR
PRZEPIORKA: Actually if I recall, Ms.
Pendergest saying that the rule says "may" not "will" or
"shall." So they've actually
thought about that very carefully and I'm pleased to see that. Dr. Cheson, you're the discussant for this
BLA. I just wanted to know if you could
sum up your responses to the questions that have been posed for us.
DR.
CHESON: I thought I was doing that
before but I'll do it again. What we've
heard is we have a drug which is potentially valuable to a select group of
patients with an uncommon disorder that appears to have benefit in about
one-third of these patients. The Phase
IV trial is having trouble accruing for a number of fairly valid reasons.
What
we've heard is that virtually everybody would like the integrity of the study
to be maintained for as long as possible and accrual accelerated hopefully by
enhancing the number of sites which are hopefully high quality sites. If it comes to the point of having to modify
eligibility criteria or any other factors, then we may have to reconsider what
we do with the study but right now that has generated some interesting
discussions about the process as a whole.
Even
though it's going to be a ten year trial, hopefully it will get done. We have some encouraging news that there is a
little blip on the accrual screen in the last few months. Hopefully that will be maintained. I don't know what else has been said.
CHAIR
PRZEPIORKA: Dr. Redman may actually
answer that question.
DR.
REDMAN: I don't know if I'm going to
answer that question but I want to ask a question that has nothing to do with
Ligand or anything. We are all dancing
around the issue saying that because a drug is approved, everybody is getting
the drug off trial and nobody is participating in the trial. In the year 2002 when seven patients were
accrued to the trial, how much of the drug was sold commercially?
DR.
L'ITALIEN: We did actually present that
earlier. We estimate about approximately
400 patients were treated with ONTAK in CTCL.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: I have three points but the
last point I was going to make goes right to this issue. Having the ability to enroll patients on a
trial does provide alternative access for patients who either can't afford the
co-payment or can't afford these drugs so there is a mechanism for patients to
get the active drug. I would encourage
the trial to continue before Pat says to shut it down and rethink the
design. So there is rationale even when
the drug can be obtained by prescription for this company to support this trial
and for us as physicians enroll, support or refer to it.
Second
point I would like to make is that the endpoint here is not survival but is objective
and verifiable response and now the crossover problem which we discussed
earlier. As Dr. Foss says taking
patients allowing them to go off study earlier than completing the eight
treatment may be a way to modify the endpoint which may overcome some of the
reticence of study centers to be involved in placebo control.
Thirdly
this is a rare disease that's usually managed.
The patients I see have had a wide variety of topical creams and topical
manipulations by the dermatologists.
Perhaps opening up the inclusion criteria and perhaps not counting any
of those topical
therapies may be a way to get this thing rolling
and getting an answer sooner. Thank you.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: Just a few issues. Dr. Przepiorka, you had brought back the
issue of the "will" versus the "may." The original terminology that we were
presented in the documentation coming into this meeting used the word
"will." We've heard
clarifications to "may."
In
my own view, I don't know that's a profound change in the sense that I would
surely hope and I believe the "may" terminology empowers the FDA to
use its proper judgment as I would hope they generally be doing to safeguard
the interest of the public and participants in trials. From my view, we are still in the same basic
position that we would be whether we use the word "may" or
"will." We have to look at
whether or not we're doing studies in an adequately timely way that will
provide answers to the questions ultimately as to whether this intervention
provides clinical benefit.
When
it comes to the issue of is there a way to streamline this trial to enhance the
ability to get the answer in a timely way, we surely do want to think about
whatever changes that we make in the context of whether it would reduce the
interpretability. Just changing the
randomization fraction does not in fact compromise the integrity of the
trial. You would though have to do a
time stratification.
To
put it simply if you started with the one-to-one randomization, then went to a
three-to-one randomization, you can't pool the data. But you can pool the information stratified
by the time periods when it was one-to-one and three-to-one and it becomes
fully interpretable.
The
issue against this which has also been stated is there may also be ethical
issues against reducing this now to a two arm trial because it changes what
fraction of the randomized participants would be on the placebo. If that's true, we have to revisit this
ethics very delicately.
In
general for study to be ethical, there has to be adequate equipoise to justify
that a participant going into this trial is being randomized to two
interventions where it's substantially uncertain whether benefit to risk of the
experimental is better than the control.
If one judges that's true and judges that it's ethical within the
context of a five-to-one or three-to-one randomization, it's very difficult for
me to understand how ethical arguments would then reverse to say if it's now
two-to-one or one-to-one it's no longer ethical.
There
are practical considerations as to how rapidly we can enroll participants. A two-to-one or a four-to-one may give us an
enhanced understanding about the safety profile of the experimental regimen. Bottomline here is it does seem to me that
the FDA and the sponsor need to be thinking through all possible with all due
urgency.
What
are the most achievable ways for us to get the answers reliably addressing
efficacy in a reasonably timely manner?
One of those ways that I would at least encourage you to continue to
think about is whether the randomization to the two arms could substantially
reduce the time. We would still have
information on that third arm during the time period up until now and it would
allow us a much shorter timeframe to finish the study.
CHAIR
PRZEPIORKA: Dr. Brawley.
DR.
BRAWLEY: I was just wondering. I'm not sure that you can have equipoise in a
drug that's been approved, even approved through an accelerated mechanism such
that you could have a placebo control trial in Phase IV. That worries me. That may be why the French decided not to get
involved in this trial.
DR.
FLEMING: It worried me in the very
beginning, ten years ago, when the concept of accelerated approval was
proposed. It was argued that we would be
able to carry out then subsequent pivotal studies post-marketing to obtain the
answer. I worried about that but I'm
assuming anyone that in fact supports the concept of accelerated approval would
say that there is the fine line here by saying reasonably to predict benefit
isn't by any means reliably predicting benefit.
Hence while it's reasonably likely hence justifying wider access during
the time period that you are validating there is still substantial uncertainty
hence making it ethical to continue randomized trials. It seems to me the logical conclusion if you
don't accept that then the logical conclusion is you're not in the position
where you can in fact do proper studies post-accelerated approval to validate
whether or not there is clinical benefit.
CHAIR
PRZEPIORKA: Dr. George.
DR.
GEORGE: There's the rub. Accelerated approval unless we're talking
this rarified atmosphere we're talking here needs approval. That's really why it's difficult. There is a fundamental disconnect between
thinking about how we can do these trials after we've had the accelerated
approval because I think maybe Dr. Cheson said this that it has the seeds of
killing itself, apoptosis.
DR.
CHESON: We call that pharmapoptosis.
CHAIR
PRZEPIORKA: Dr. Martino.
DR.
MARTINO: Part of the problem here is the
actual word "accelerated." To
most of us who don't sit on committees like this, acceleration means that
there's a really good reason why you are allowing me to do something. In fact that's such a good reason that you
quickly allowed me to do it.
The
actual psychological implication and understanding of the word to most people
is that there's actually probably a better reason why you have allowed me to
use this drug. Those of us who realize
that no one really understands this conception are actually quite correct. Approval means approval. You allowed me to get there even quicker with
this process. It must be a better
drug. That's the assumption that most of
us make and that's the struggle we are having.
It's that people take it that way and act on it from that perspective.
CHAIR
PRZEPIORKA: Dr. Weiss, do you have a
comment?
DR.
WEISS: I know you probably discussed it
some this morning but certainly it seems like in oncology - and we were in a
similar scenario just about a month ago that Dr. Fleming will very well
remember with a different disease setting where we were talking about doing the
confirmatory trial in a somewhat different population where the feasibility
perhaps of doing a placebo controlled trial may be more palatable.
That
is somewhat of the situation here. Even
though it's very similar you are talking about a somewhat different population
than the approved indication for ONTAK currently. I'm just wondering if anybody had any comment
on that particular aspect.
DR.
FLEMING: That's a very good point,
Karen. I personally do struggle with
this idea of saying we believe there is enough evidence that we in fact want to
make it available to the public. Then we
think it's ethical to randomize unless we are in a setting where we think
reasonable people will differ as to what
level of evidence they think you need to have to justify use of the
intervention hence allowing certain people to say I want to use it, certain
people to say I don't want to use and certain people to say I'm uncertain. If that is the real world's scenario then it
is ethical. It is possible then to
enroll participants into studies like this even while the intervention is made
widely available. Clearly in that
scenario, it doesn't matter whether it's one-to-one, three-to-one or
five-to-one randomization. It's either
equally ethical or equally unethical.
Karen,
the situation you referred to was a situation a month ago where there was a
perspective that further advanced patients would benefit but intermediate
advanced patients it was unclear. Those
intermediate advanced patients then may well be willing to accept equipoise and
be randomized. That is a practical way
this could be done.
CHAIR
PRZEPIORKA: Ms. Mayer.
MS.
MAYER: I just want to echo Dr. Martino's
comments about patient perceptions about what accelerated approval really
means. Even as an educated advocate
prior to some of my preparatory reading for this meeting and prior to reading
the data on the individual drugs involved, my perception in fact has been that
we were talking about drugs that show unusual promise. That's why they are made available prior to
the completion of clinical studies. This
is a widely held perception that is perpetuated by the media and it's something
that needs to be factored in.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: I don't know for analogies
help. Surrogates have been widely used
in other areas besides oncology like lower blood pressure and lower cholesterol. Nobody has felt it's an ethical difficulty to
confirm that lowering cholesterol really is good for you. Probably hundreds of thousands of people have
been randomized into a placebo control trials to see what populations that's
true in. That was also true of
hypertension until it became obviously that there really was a benefit when it
did indeed become unethical. As long as
there's a reasonable question among honest people about whether there's a real
benefit, I think the ethics are fairly straight forward. The public perception is another matter. They may not want to be in them. That's more difficult.
CHAIR
PRZEPIORKA: I would agree with you in
that here's a situation that would be applicable to the principles that Dr.
Pazdur mentioned earlier which is maybe the Phase IV commitment trials don't
have to be exactly the same perhaps as in an earlier disease, maybe not placebo
controlled but randomized against topical therapy earlier on.
DR.
TEMPLE: There's no question. That's one of the reasons we have allowed
that because you can get them done.
CHAIR
PRZEPIORKA: Dr. Keegan.
DR.
KEEGAN: Just another comment on the
equipoise issue. In the original
accelerated approval, there was exquisitely collected data on response rates. It was actually one of the best applications
I believe I've ever seen in terms of dealing with a difficult to assess
disease. Photographic techniques were
standardized. The grids. It was actually exquisite.
In
addition, there was a number of things collected on that trial as are being
collected on this trial to collect patient symptoms of a variety, pruritus,
global severity assessment by physicians and concomitant medications
usage. What was interesting was that
although patients did in some instances report decreases in symptoms, we could
not in most instances in most of the responding patients observe a documented
decrease in use of concomitant medications to treat those symptoms which again
led us to the concern about what are we seeing here.
There
was some correlation in the patients with the most dramatic and complete
responses but it was bordering on anecdotal in this entire dataset. Again the thought was it was hard to put that
in context and a placebo controlled trial collecting the same kind of
information would likely help us to put that concomitant medication in use
context. I also mention that because of
the concern about using response rates as an endpoint in that collection of a
lot of the patients' symptomology data in the concomitant medication use we
expect will bolster that information and will provide us with an ability to put
those response rates in the context of clinical benefit to patients.
CHAIR
PRZEPIORKA: Dr. Pazdur.
DR.
PAZDUR: I'd just like to draw your
attention while everybody's laying crepe on this process to the successes of
the process. Take a look, young man,
West to where the four indications where we were able to basically demonstrate
clinical benefit. There are some lessons
that we can gain from there.
It's
clear studies are better if they are on-going.
We've repeated this. I almost
sound like a machine saying this over and over again. The other thing that Donna brought out and I
brought out previously was that most of these were being done in earlier or
different stages of the disease.
For
example if you take a look at the original Irinotocan trials, it was approved
with a 10/15 percent response rate in 5-FU refractory diseases. Basically the study that the agency
negotiated for clinical benefit was the first line trial. However in Europe there was best supportive
care against CPT-11 in the same stage.
We weren't even aware of those trials when the drug was approved I don't
believe. I wasn't working at the agency
but it wasn't widely known about the trials at the time of approval. The actual letter states that the first line
trials were going to be the confirmatory trials. It's important that we keep in perspective
that there might be other ways of addressing this issue.
Also
as we lay crepe on this process here, it's important for us to understand that
really an important part of this is to get these therapies out to people
early. I don't think that we should
undermine the benefit of people getting therapies early.
Remember
the confirmatory studies are important.
Believe me I'm the one that wanted this meeting. They are fundamental to the process but
they're not the only way to spell success of a drug. Ultimately we want to know this answer. But to say that these therapies are
unsuccessful in a bigger picture here of oncology therapeutics in the United
States would be really selling the process short.
I'm
making an emotional plea here because I really think that one has to step back
and take a look at the total picture not just has the confirmatory trials been
done. Yes, I want them done but success
is more than passing one test. Anyone
that has any child or children know the answer that the success of a child
simply isn't in their report card. Thank
you.
CHAIR
PRZEPIORKA: Thank you, Dr. Pazdur. I hope we're not giving the impression that
we're trying to drape crepe on the accelerated approval process.
DR.
PAZDUR: Well, you're doing a great job
of it.
CHAIR
PRZEPIORKA: This committee pretty much
has a very good record of dealing with the accelerated approval of drugs that
come here. We are happy to provide our
insight into what should go into Phase IV commitments and if I speak for myself
we are pleased with the way the division is handling Phase IV commitments. Any other comments?
DR. CHESON: I can make one final glib comment. Reflecting on my two colleagues here who
don't like the name accelerated approval because in fact it does suggest that
you zipped it through and you are moving it fast, unconfirmed approval. Throw some crepe on that one.
DR.
CARPENTER: Conditional approval.
DR.
CHESON: Conditional approval.
DR.
WEISS: There was actually some
discussion about this. Bob Temple would
remember. Wasn't there some thought that
it was going to be called conditional at first but then there were problems
with that?
DR.
TEMPLE: That name turned out to be
politically incorrect. And it's
accelerated. We wouldn't have approved
it without it so it is accelerated.
CHAIR
PRZEPIORKA: Dr. Keegan or Dr. L'Italien,
do you have other questions for the committee?
DR.
L'ITALIEN: No, I just would like to
express our gratitude to the committee and also to the agency for some lively
discussion today. Certainly it is our
goal to bring these studies to conclusion as rapidly and successfully as
possible. We pledge to work with the
agency to keep on top of this and to try to complete these studies.
CHAIR
PRZEPIORKA: Thank you. We will end this session and have a short
break. Be back here by 2:55 p.m. Off the record.
(Whereupon,
the foregoing matter went off the record at 2:50 p.m. and went back on the
record at 3:00 p.m.)
CHAIR
PRZEPIORKA: On the record. If the members of the division would like to
take their seats we can get started please.
We'll start with Ms. Clifford reading the Conflict of Interest
statement.
SECRETARY
CLIFFORD: The following announcement
addresses the conflict of interest issue with respect to this meeting and is
made a part of the record to preclude the appearance of a conflict. Based on a review of the submitted agenda for
this meeting and all relevant financial interests reported by the Committee
participants, the Agency has determined that there is no potential for a
conflict of interest at this meeting.
In
addition, we would like to note that George Ohye is participating in this
meeting as the Acting Industry Representative.
Mr. Ohye would like to disclose that he previously served on the Board
of Directors of the U.S. Bioscience, the developers of Ethyol prior to its
acquisition by MedImmune. He has stock
options in MedImmune.
In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participant should exclude himself or herself from such involvement and the
exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose any
current or previous financial involvement with any firm whose products they may
wish to comment upon.
CHAIR
PRZEPIORKA: At this time if we
could ask the new members from the
division to introduce themselves please.
DR.
FARRELL: Ann Farrell, Medical Officer.
DR.
WILLIAMS: Grant Williams, Deputy Director.
CHAIR
PRZEPIORKA: Thank you. Our next presentation will be given by Dr.
James Pluda from MedImmune regarding NDA 20-221, Ethyol reduction in cumulative
renal toxicity associated with repeated administration of cisplatin in patients
with advanced non-small cell lung cancer.
DR.
PLUDA: Thank you. As just stated, my name is Dr. James
Pluda. I'm head of Clinical Oncology for
MedImmune and I will be discussing the Ethyol Non-Small Cell Lung Cancer
Indication.
First
I would like to briefly review what I'll be discussing today at the
meeting. I'll be presenting the
mechanism of action of Amifostine and the indications for which it is fully
approved followed by additional information regarding the accelerated approval
for nephroprotection in non-small cell lung cancer patients receiving platinum.
I
will then present the results of the Phase III trial performed to meet the
obligation of the accelerated approval strategy which although it did meet the
nephroprotection endpoint did not meet the endpoint of demonstrating lack of
tumor protection. Lastly I will discuss
our continuing obligation to fulfill the accelerated approval and some of the
issues involved.
This
slide shows the mechanism of action of Amifostine. Amifostine is an organic thiophosphate
developed by the Army initially to protect soldiers from the effect of
radiation. It serves as a pro-drug being
metabolized to its active form which is WR-1065 by membrane-bound alkaline
phosphatase at the surface of cells.
WR-1065 is a free-thiol which then is taken up into the cells and
scavenges oxygen-free radicals and free radicals formed by chemotherapy as
well.
Pre-clinical
data indicate that there is a differential protective effect of amifostine in
normal tissue compared to tumor tissue.
This slide shows that amifostine is preferentially taken up by normal
tissues compared to tumor tissue. I'd
like to point out that the concentration over here is a logarithmic scale. As you can see, Amifostine's highest
concentration occurs in the kidney. In
tumor tissue at 30 minutes which is typically when the chemotherapy, radiation
therapy is given after the initial administration of Amifostine. There was a greater than two log difference
in concentrations. Even as far as 90
minutes which is well after the end of the chemoinfusions or the radiation
therapy, there is still greater than a log difference.
Amifostine
has been formally approved for the prevention of xerostomia from radiation
therapy in post-operative patients with head and neck cancer where the
radiation field involves the majority of the parotid gland. In addition it was approved for the reduction
of cumulative renal toxicity associated with cisplatin in advanced ovarian
cancer patients.
Now
U.S. BioSciences was granted accelerated approval for Amifostine for the
prevention of cisplatin nephrotoxicity on the basis of a Phase II trial that
contained 25 patients. This was in
non-small cell lung cancer patients with locally advanced or metastatic disease
stage IIIb/IV who were receiving vinblastine, cisplatin and Amifostine.
In
order to fulfill the accelerated approval, the requirement for full approval, a
Phase III trial with non-small cell lung cancer patients administering
cisplatin and Amifostine that demonstrated both nephroprotection as well as
lack of tumor protection was required.
This post-approval commitment was WR-0053 which was initiated by U.S.
BioSciences in December 1994 and was on-going at the time the accelerated
approval was granted.
This
is a Phase III randomized control trial in the same population as the Phase II
study locally advanced metastatics, Stage IIIB or IV non-small cell lung cancer
patients. Patients received cisplatin
and vinblastine with or with Amifostine.
The co-endpoints of this trial were the demonstration of no reduction in
anti-tumor efficacy with a reduction in Cisplatin-related nephrotoxicity.
Shown
here are the results of the nephroprotection endpoint of the study. The nephroprotection by Amifostine and
cisplatin treated patients was confirmed by this trial. As you can see, the control patients had a 49
percent incidence of nephrotoxicity which was defined as a greater than or
equal to 25 percent decrease in creatinine clearance from baseline. Whereas the Amifostine treated patients had
only a 28 percent incidence of nephrotoxicity, a difference of 43 percent. If you look at nephrotoxicity two different
ways, either by total cisplatin dose or by cumulative cisplatin dose to the
onset of nephrotoxicity, there was still a significant difference between the
control arm and the Amifostine arm.
This
slide shows the results of two of the three parameters that were necessary to
demonstrate no effective anti-tumor activity in the protocol. No difference was observed in the response
rate or progression-free survival in the Amifostine patients compared to
control. You can see that in the control
arm there was a 32 percent response rate, 30 percent in the Amifostine
arm. The median progression-free
survival was 4.73 months in the control arm and 4.14 in the Amifostine arm.
This
slide shows the results of the third parameter, overall survival. The median survival for the Amifostine
treated patients was 8.75 months. For
the control patients, it was 9.93 months.
Also shown here are Kaplan-Meier curves that depict that outcome. There's a slight separation at the end of the
curves as you can see here.
Additional
analyses were done of the data in order to see what factors might of influenced
this observation. A covariant analysis
on survival indicated that there was an interaction between treatment and
performance status. This table here
delineates those data. The biggest
difference was between the Amifostine ECOG performance status zero patients and
the control ECOG performance status zero patients. As you can see, the control was 17.2 months
whereas the Amifostine was 9.8 months which was essentially identical to what
was seen in historical controls. In the
ECOG performance status one patients, the control and the Amifostine were the
same and again were the same as in historical controls. The prolonged 17.9 months survival of the
control performance status patients is clearly different from what might be
expected in the population and is likely responsible for what we saw in the
separation in these curves.
What
is depicted here is the collective experience with the Phase III Amifostine
trial. The hazard ratio is in the 95
percent confidence intervals for all five Phase III trials including 53 which
are up here. The turquoise bars represent the hazard
ratios and the horizontal line represent the 95 percent confidence
intervals. The hazard ratio is greater
than one which is to the right of this vertical line and they all favor
Amifostine. As you can see, all of the
confidence intervals overlap one.
If
we look at some of the individual studies, we see WR-0056 which is a study in
patients with non-small cell lung cancer.
It's the exact same population, IIIb/IV patients, as 0053. Although this trial didn't meet the endpoint
of the trial which was hematological protection from carboplatin and
paclitaxel, the survival data from this trial are instructive. In fact if you look at survival between the
Amifostine control arms there is absolutely no difference between Amifostine
control or even historical control regardless of performance status.
WR-0001
was the ovarian cancer study that was used in order to grant Amifostine its
initial full approval for cisplatin nephroprotection. There are two other studies 0038 and 9001
that were studies that administered radiation therapy. This was the head and neck study that was
originally used to get the positive approval for prevention of xerostomia as
well.
Although
these trials involve different patients with different treatments, we do not
see anything here that would suggest that there is an overall or general
survival issue with Amifostine. Be that
as it may, the overall conclusion that can be drawn from the results of 0053
are that cisplatin nephroprotection seen in the ovarian and non-small cell lung
cancer trial were confirmed.
Looking
at the anti-tumor efficacy endpoint, two of the three parameters for
demonstrating no effect on anti-tumor treatment were met: no difference in the
response rate and no difference in the progression-free survival. The difference in median survival did not
meet the protocol defined endpoint and is the reason that the lack of effect on
anti-tumor efficacy endpoint overall was inconclusive and that WR-0053 did not
meet the accelerated approval obligation.
Now
the guidance that we have received from the agency is that we still have an
obligation to perform a new cisplatin-based study in patients with non-small
cell lung cancer, demonstrating the co-primary endpoints of nephroprotection as
well as non-inferiority of survival or a survival surrogate.
It
is this non-inferiority endpoint that drives the sample size for such a trial.
The assumptions for calculating that sample size are that non-inferiority
would be determined by a one-sided 97.5
percent confidence interval and that also there would be the retention
of at least the 50 percent of a treatment effect seen in the literature for the
regimen that's being used in this study with Amifostine.
Based
on these assumptions, if non-inferiority of a surrogate that is of survival
response rate were used as the primary endpoint, the trial would take about
1,150 patients. If one had used the
actual survival as the primary endpoint, the trial would take approximately
2,600 patients. To demonstrate
nephroprotection alone with 85 percent statistical power would take
approximately 400 patients.
The
main challenge in the current environment to the performance of another
cisplatin trial in non-small cell lung cancer of this size is accrual. Now there's a changing pattern of cisplatin
utilization in this population with the decreased use of high dose
regimens. Carboplatin is being
substituted more frequently for cisplatin in some of these regimens. There are a number of high priority
therapeutic agents being evaluated in this same population that will compete
for accrual.
Based
on the design presented and with the patient pool of non-small cell lung cancer
patients receiving platinum in the United States of approximately 700 per year
and an accrual rate of 240 patients per year, this trial will take
approximately 6.5 or more years to complete.
In
summary, the nephroprotection from cisplatin toxicity by Amifostine has been
established. Conclusive proof of lack of
tumor protection by Amifostine has not yet been established. Therefore a definitive trial demonstrating
lack of tumor protection in patients with non-small cell lung cancer receiving
Amifostine/cisplatin is required.
We
are currently confronted with the challenges of meeting that obligation and
look forward to any comments or guidance that the committee may have to offer
us. Thank you very much.
CHAIR
PRZEPIORKA: Dr. Williams, do you have
comments for the committee?
DR.
WILLIAMS: Yes, thank you. One of the problems with this application in
terms of tumor protection is that our approach and our knowledge about this
field has progressed over the years.
Tumor protection is one issue and non-inferiority studies are another
issue. Both of those have become issues
of concern to us.
Our
first experience with this was with Zinecard.
We brought that application to the committee twice. The first time there was a P-0.001 difference
in response rate in breast cancer with Zinecard which led to a very heightened
concern that the possibility of tumor protection is there especially when
you're not quite sure why the drug would protect the patient and not the
tumor. So we have a heightened concern.
With
the first approval in ovarian cancer, it was on a very small study by today's
standard. It honestly didn't really rule
out tumor protection. It was a little
before we developed our current sophistication.
With
this next accelerated approval, we began to apply our current standards to say
you really do need to prove that you're not protecting the tumor at least in
one tumor and do it well. That's why we
stuck by our guns on this and not said that we're going to go ahead and convert
approval without a really good proof by today's non-inferiority standards that
there's no tumor protection.
The
other difficulty is the lung cancer drugs are only marginally effective. So that the effect size you see from these
drugs is so small that to show non-inferiority becomes a big challenge. Those are the issues that are behind our
insistence to pursue this exercise and to try to insist that this drug is
proved in the clinical trial setting which I don't really understand why the
drug should protect only the patient and not the tumor.
CHAIR
PRZEPIORKA: I wanted to ask a question
regarding trial design that I hope would engender some discussion but also
because I am concerned about requiring a trial of 1,000 patients to prove
non-inferiority. The issue that came up
in the first trial had to do with the secondary endpoint and a safety
concern. In order to relay that safety
concern, would a valid trial be one not to show non-inferiority but to show
inferiority and then reject the null hypothesis?
DR.
WILLIAMS: No, actually we're using the
term "non-inferiority" here.
That's glorifying the term a bit.
As Dr. Temple can tell you, in the other fields when we use the term
"non-inferiority" that means almost exchangeable. We're just saying is there some effect here
when we do this sort of a comparison.
I
can bring up another issue that relates to this that might in some settings
allow a different trial design. My
personal view is that what we're looking at is tumor protection. We're not looking at some extraneous
potential effect on survival that this whole issue is related to tumor
protection. So my view is that one can
look for the most sensitive indicator of tumor effect and try to show that it's
not abrogated. That would be my
approach.
Now
this survival effect may just totally be another spurious thing that we saw
earlier. But in view of it, that one
should take note. The trial was not
designed by current standards to demonstrate non-inferiority by any endpoint
for the previous trial. Just because you
didn't see a difference, that doesn't mean that you've established that the
drug does not protect the tumor. It only
means you didn't see a difference.
To
demonstrate non-inferiority to that, you need at least to know what is the
effect the drug has and can you be sure that if the drug wasn't there that
you'd see a difference. That's the
minimal standard. You did need
statisticians to help you decide how many patients do I need to study to show
that I've had any preservation of effect.
We're not really asking for a very strict non-inferiority here. We're asking for at least a gross indication
that the effect has been retained.
DR.
PAZDUR: One of the aspects I would like
to discuss and maybe Gain (PH) could answer this question also if we look at
another endpoint other than preservation of survival for example response rate
preservation what would be the numbers that would be required?
DR.
PLUDA: Yes, as I showed if we look at
response rate it would be 1150 patients.
For survival it would be 2600 patients.
DR.
WILLIAMS: Did you mention time to
progression?
DR.
PLUDA: The calculation here, we only
found one randomized control paper in the literature that compared the
chemotherapy that we would be using as a singlet to as a doublet in combination
with cisplatin. There was only one
article. That was a vinblastine plus or
minus cisplatin and they didn't give time to progression data in that
article. We only had response rate so
that's why we didn't have the time to progression.
CHAIR
PRZEPIORKA: I hate to beg the question
but if in fact they chose to say let's do a study to show that Amifostine is
bad rather than good and powered it to show that it actually decreased median
survival by four months which is what the first study showed, would a negative
study of that design be of any help?
DR.
WILLIAMS: I think you are
misunderstanding that first study. We're
not just demonstrating that it's wrong.
That isn't our goal. Our goal is
to demonstrate that Amifostine does not protect tumor.
DR.
TEMPLE: It's not what she's asking. You're asking whether if they could show that
it didn't make a four months worse would it be good enough. Is that right? That goes back to the old days. I don't know what the effect of the drug
without any Amifostine is. Let's say
it's only two months. Then ruling out a
difference of four months isn't really very helpful because four months is
larger than the whole effect of the drug.
So you get into these massive studies when you do so-called
non-inferiority designs.
Just
as a general rule, we try to calculate what the effect of the control agent is
and then we take some fraction of it like 50 percent and say we want to rule
out a loss of that. Because if you lost
all of that, then you really wouldn't be doing any good. But it does produce these massive
studies. I thought Grant was going to
say that he thought looking at response rate was reasonable. Is that what you meant?
DR.
WILLIAMS: Right.
DR.
TEMPLE: Well, looking at response rate,
the difference between no treatment and treatment on response rate is huge,
compared to the difference in whatever you are looking, for example tumor-free
survival. So it's a much smaller
study. Was the 1100 patients based on 50
percent retention?
DR.
PLUDA: Yes.
DR.
TEMPLE: Yes. Well, that's tiny compared to what they have
to do. So, one of the things that eventually
we ought to all talk about is with these tumor protectants how sure do we have
to be. Would preservation of response
rate be good enough, given that it's the same drug after all? That's worth thinking about because it can
become impossible this way.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: I need help here from
doctors, statisticians, Dr. George and
Dr. Fleming. Here we have a series of
randomized trials, one of which shows this potential decrement in outcome
related to the drug and the others in one and the same disease -- others in
different diseases -- fail to show any such suggestion of adverse effects. Can you speculate of some statistical quirk
here that could explain this, short of doing a 2600 patient trial? Steve.
DR.
GEORGE: Speculate?
DR.
CHESON: Or whatever you statisticians
call it.
DR.
GEORGE: Right. Well, part of this is looking at the studies
which are in different areas and different diseases and different designs. But it's hard to know in that case. It looks like they all overlap the one. The issue though that is a fundamental
problem here, I guess, in this type of study is you have something that you can
show fairly easily perhaps that protects the toxicity but it's very difficult
to show that it doesn't have a decrement in some other important --. It's very difficult in terms of just size and
studies that have to be done. That's
what Greg was getting at.
There's
no easy way out of that, short of just loosening the standards that you would
require. For example, if you looked at
just these results, you might just say looking at response rates. I'm looking at one of these earlier
slides. I don't know which one it is. There's the slide with response rates and
progression-free survival.
If
you look at those confidence intervals by sort of normal -- by common
man-on-the-street kind of thinking, you ruled out a decrement of about 11
percent, even though the response rates themselves are virtually
identical. You ruled out a bigger
decrement than 11 percent but 11 percent -- if it's really that big -- that's
probably too big for what you want. You
can do the same thing with progression-free survival.
So,
in short -- but that's the kind of logic you have to use. If you are trying to protect yourself against
the potential loss of any kind of effect, 50 percent is pretty big. And so you reach big numbers. I don't know an easy way out of that, short
of loosening that standard. I don't know
if you want to do that.
CHAIR
PRZEPIORKA: Dr. Fleming.
DR.
FLEMING: Bruce, your question about how
to interpret the results of the 0053 trial in the context of the other studies
is difficult. The 0053 was the targeted
study. It was the primary study. It was in the indication in which we were
focusing, and external data is always of some relevance. It's somewhat subjective how we weigh it in.
What
is the relevance of what we see in head and neck and in other disease settings,
relative to what we are seeing in small cell?
Usually when we look at efficacy of platinum, we would establish the
efficacy of platinum based on data in non-small cell, not whether there is or
isn't efficacy in other settings, unless we think there is a
pathophysiologically related mechanism here that's sufficiently close that
there's relevance. I would say that
there is some relevance.
But
ultimately it was prudent. The way this
was being set up was to conduct a study of appropriate informativeness in this
setting to understand whether we had the renal protection and that we didn't in
fact compromise efficacy.
Donna,
let me come back to your point, which is really a very important one. For me it's deja vu ODAC 1986, which is can
we look at just saying we're not meaningful worse. I say that because in 1986 this committee was
presented mitoxantrone in advanced breast cancer. Four small studies were done that showed we
had three months less survival than adriamycin, but we weren't statistically significantly
worse. And so there was a judgment that
as a result approval should be given because we had equivalence, because we
hadn't been proven to be worse.
Yet
you step back and say adriamycin itself probably provides three months
improvement in survival. So for three
months worse than something that provides three months benefit, even though
we're not significantly worse, logic says we're the same as nothing. I can get rid of the cardiotoxicity,
myelosuppression, nausea and vomiting of adriamycin by just stopping the
adriamycin.
Here
the fundamental challenge -- and it's not just because this is accelerated
approval; this is always the case in chemoprotection trials -- what we have to
ask ourselves is: okay, we can reduce
from five in ten patients having significant renal toxicity to three in ten having
significant renal toxicity. Presumably
we could get that reduction by having some level of reduction in the
cisplatin-based regimen in this setting.
If
we did, how much less efficacy would we have with that level of reduction? Fundamentally, I want to be sure here that
we're not giving sufficient levels of platinum-based regimens to induce renal
toxicity in half the patients, and then we negate that in two of the five. So you still have toxicity in three of ten
and not still have the benefits of that regimen.
And
so what we have to do then -- it's not good enough just to say, are we
significantly worse -- do a small trial, and you will in fact not be able to
conclude you're significantly worse even if you've lost all the benefit. It's not easy, but we do have to be able to
have some level of confidence that we get the chemoprotection without the price
of losing the efficacy.
So
then we step back and say, how do we do it.
It's not easy. When we look at
this, is it enough to look at response rates?
Well, response rates don't show much difference; but there is a
difference in duration of response. The
duration of response is one-third longer when we haven't given Ethyol. There are different small numbers. CRs are four versus one. And there's a difference of one month in
survival -- or basically one and a half months in survival, and you have a
relative risk of 0.83.
So
when I look at all of this, I would say just the response data alone may not be
capturing the nature of how we are compromising the benefit here. Bottomline is, I think the FDA is right on
target by saying that whether this is accelerated approval or not -- and I
think we've heard that the fact that it's accelerated approval doesn't mean
that we should have weaker standards for showing that we've established favorable
benefit-to-risk -- in a chemoprotection study we have to show the
chemoprotection and, as Stephen George says, that's the easy part.
The
tougher part is to be able to show it selectively achieves such that you
couldn't have been able to achieve that same chemoprotection by just a
dose-response dose-reduction of the active agent. Here we are protecting patients to ensure
that when we actually have made it as hard as it is to get an advance here we
have an advance. We have regimens that
improve survival. Let's not lose that
advance if in fact we are trying to do so with chemoprotection in ways that
might cost us more of the benefit and efficacy than we are willing to give up.
CHAIR
PRZEPIORKA: I just want to give comments
on your question because there has been a drug before this committee in the
distant past that I recall that also had a quirk of randomization where the
eligibility of criteria were heterogenous and where the control arm had a good
prognosis population as opposed to the treatment arm. That's some of the data he was alluding to
when he was showing his own data which was that the control arm had a better
survival than the historical controls.
That is just a fluke which is why I'm concerned that perhaps they're
being held to a higher standard than they should be if they have to go and do
an entire non-inferiority study instead.
DR.
WILLIAMS: The database that's described
here is difficult because it just so happens that one study is the one that is
in the indication and with the drug that it was proved. Carboplatin has no proved indication. We're protecting nephrotoxicity so the data
that comes from carboplatin may be you want
to make that extrapolation or maybe you don't.
Radiation
is another kind of treatment. Maybe you
want to make that extrapolation or maybe you don't. Head and neck is another tumor. I don't think they are overwhelming
supportive. Then the ovarian study is quite small if you look the size of
those confidence intervals for the other approved indication.
I
understand what you are saying and we really do have to make the fundamental
decision. We have and that's why we are
applying this standard about what we are going to do with tumor protection
agents. We don't do this for anti-nausea
agents. It's a clearly extremely
different mechanism where we don't expect that it's going to interfere with the
tumor. What we don't understand with
great confidence why it shouldn't protect the tumor then why shouldn't we
require them to make sure that they are retaining at least a moderate fraction
of the benefit from the drug.
CHAIR
PRZEPIORKA: Dr. Temple.
DR.
TEMPLE: Having said that and not
disagreeing with Tom in any way about the importance of it, I would add to the
list of things we ought to bring to you for further discussion which is now
getting very large the question of whether there are some other things one
could do here. For example given that
it's the same drug, is tumor response more plausible than it might be in some
other cases as an indicator of similarity?
That's one. I'm not trying to say
what the answer should be.
The
other is if you really think that a therapy might interfere with the anti-tumor
activity of a drug, maybe tumors of several different kinds are relevant to
that and it's worth thinking about all the data together even though you
wouldn't do that if you were trying to make a tumor treatment claim in each of
those. That might be relevant to the
mechanism here. You think that if it
interferes with one it might interfere with the other. Again I don't know that we know that.
Those
things we're thinking about because it becomes extraordinarily difficult to
develop a protectant. If you want to
protect it in several different tumors, you have to do all over again in each
tumor. It's harder than working up a
drug for treating something. So you can
make it so difficult that nobody bothers too and that's not a good outcome.
DR.
FLEMING: I would say it would be equally
hard to working up another drug that you would look at as a replacement drug
where you had to do a non-inferiority comparison. If Agent A is established and now you come
along with B and you want to look at B replacing A, it would be equally as
challenging as that setting.
DR.
TEMPLE: Yes, but that's very challenging
and very difficult. Those are two
questions off the top of my head that we need more discussion on. I'm sure people will think of more.
CHAIR
PRZEPIORKA: Dr. Blayney.
DR.
BLAYNEY: Again I enjoyed your comment,
Dr. Fleming. Perhaps you can help me
with a question. If you have a 30
percent response rate like you do in lung cancer and you're trying to detect
the non-inferiority adding a loss or protection with your protector, what if
you move to a 95 percent response rate like one would have with testis
cancer? Does that make the study size
smaller?
DR.
FLEMING: What really drives this more is
what's the margin. How much less are you
willing to have before you say it's a clinically meaningful loss? That drives the sample size more than anything
else. In my view what saves us and we
don't think about it a lot in a non-inferiority setting is if we actually think
we might be a little better. Then we can
rule out that we're meaningful worse without taking a very large sample size.
I
step back in this setting and I read the conclusion paragraph that we were
given by the sponsor as the rationale here.
The sponsor is saying "Cumulative renal toxicity may have a
significant and negative effect on the efficacy of cisplatin administration
because of dose response, dose reductions, treatment delays, treatment
discontinuations, life threatening fatal renal toxicity," etc. If reduction is working and technically it's
a surrogate in creatinine clearance, 25 percent, if this benefit does translate
into these targeted benefits then logically doesn't it follow that with this
chemoprotective agent that this regime ought to have an enhanced benefit
because you're not having to reduce the effective cisplatin-based regimen.
In
fact, there was a hypothesis in here that you might be better ruling out a
quality or if we're the same ruling out we're worse. With a truly effective chemoprotective agent
that's doing what you want, isn't that an agent that gives you a better way to
deliver the effective interventions more fully in which case we would expect in
truth a somewhat better result? It
doesn't have to be statistically significantly better but just modestly better. This allows you now to rule out you're
meaningful worse with a much smaller sample size.
Part of what troubles me here is
the aggregate data in which one trial could be a false negative conclusion show
a negative trend even in the context of validated renal protection which should
have I would have thought allowed us to more fully treat these patients. I would have thought we would have seen a
positive trend. If truth is a positive
trend, to answer your question, we can rule out a negative trend without an
inordinately large sample size.
DR.
BLAYNEY: But your remark is predicated
on a dose response in lung cancer. With
platinum in lung cancer, there's probably not a dose response. It may be four to six cycles.
DR.
FLEMING: I was just quoting the
sponsor's remark.
DR.
BLAYNEY: Yes. I'm sorry.
The point is that it does require either a dose response or a cumulative
benefit. I don't think that in lung
cancer anybody believes that's the case.
DR.
FLEMING: The other argument that I would
always make in a non-inferiority trial is the margin should in fact be a bit
more flexible if we are truly providing tangible benefit in ways other than
what is reflected by that endpoint. We
really are providing important symptom relief for reduction of major important
documented side effects. Those are out
there and documented. My own view is
that should allow for a bigger margin.
So
we did see a surrogate here. What are
some of the tangible things that we can add that we can say are documented to
be better for this intervention group that got the Ethyol? To the extent that we can document ways that
this group is better, I would argue to the FDA that a somewhat larger margin
should be allowed. To the extent that we
can't, then a more rigorous margin should be required.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: We focused on the ability of the
agent to protect against nephrotoxicity at higher doses and want to preserve
efficacy at higher doses. But sponsor
noted that lower doses are much more commonly given. What data is there for using this agent as a
nephroprotectant in lower doses? What's
the magnitude of the difference there?
DR.
PLUDA: The only nephroprotection
significant data that we have is from the ovarian trial, the non-small cell
lung cancer trials. Other trials with
much lower doses of cisplatin have not as yet have been performed.
DR.
KELSEN: So if you give cisplatin to a
human whether it's for lung cancer or not if doses of 50 to 75 per meter square
which would be used fairly frequently now, how well does this agent protect
against nephrotoxicity in those patients?
DR.
PLUDA: Those studies have not as yet
been performed.
DR.
KELSEN: If the magnitude of the
difference is very small and you have any worry about losing efficacy, the
balance shifts.
CHAIR
PRZEPIORKA: Dr. Blayney, would you like
to address the questions?
DR.
BLAYNEY: Has accrual to an on-going
trial been satisfactory for timely study completion? I think so but the field really in lung
cancer has been pointed out that it's moved.
Most people treat if they use a platinum agent with carboplatin not
because really of nephrotoxicity but because of the neurotoxicity and some of
the other toxicities. That again makes
trying to complete this trial more difficult.
We're
likely to see other agents and we have seen other agents in the last few years
that have substituted for either of the platinums. That is going to make complete even more
difficult for them.
Other
strategies that they might consider where I mentioned the testis cancer thing
that would require a complete trial rethinking of the trial design. Perhaps that's not practical but these
patients are likely to live a long time if they do develop toxicity. Testis cancer patients will live for a long
time with that toxicity. So if they can
be protected, that may be a useful thing.
Perhaps
also including the other solid tumor versus platinum which has been used and
you've alluded to it earlier is ovary cancer.
If the trial can be opened up to include ovary cancer, it might be a
reasonable strategy and also cisplatin combination of choice as an inclusion
criteria. Perhaps you've already thought
about that.
Thirdly,
has the approval impeded the ability to conduct a planned trial? I don't think so. It's more approval of other agents rather
than the approval of Amifostine. I've
already alluded to other alternative designs which might be contemplated.
CHAIR
PRZEPIORKA: Other comments from the
committee? Dr. Redman.
DR.
REDMAN: Do you have data that suggests
that those patients that were on the control group actually got a total cumulative
doses of platinum?
DR.
PLUDA: Total cumulative doses of
platinum?
DR.
REDMAN: Yes.
DR.
PLUDA: What we did have was the data
that demonstrated that the time to the cumulative dose of platinum before the
onset of nephroprotection which is where you would begin to start to dose
reduce this platinum. There was a
significant difference in the cumulative dose as well as the dose of platinum
that it would take before the nephroprotection actually began. As you can see when you got up to 360 mg/M2
there that there was a significant difference in the amount of toxicity. That would presumably relate to patients
being able to get more cisplatin than patients who did not have nephrotoxicity
and required dose reductions.
DR.
REDMAN: I'd just offer another
hypothesis to Dr. Fleming's that maybe the survival difference is due to the
fact that the control group got less cisplatin.
CHAIR
PRZEPIORKA: Dr. Cheson.
DR.
CHESON: Could you give me some idea of
the magnitude of the nephrotoxicity in both of the arms? How reversal was it? In other words, is it just that you get a 25
percent decrease in your clearance or is it something that's significantly
worse than that?
DR.
PLUDA: We also did an exploratory
analysis looking at 40 percent decrease in creatinine clearance as well. In that analysis, there was a still a
significant difference between the Amifostine and the control arms as you see
here. So even if we looked at a much
higher standard for prevention of nephrotoxicity, we still were able to
maintain a significant difference between the arms. You can see the cumulative dose in
nephrotoxicity was significantly different again between the two arms. That was to 40 percent, not just 25 percent
reduction.
DR.
PAZDUR: But was some of this
reversible? I think that what Bruce is
getting at. You may have a P-value there
but is it clinically meaningful however you want to term that?
DR.
REDMAN: That is true. When you administer cisplatin if you do
serial creatinines on them in the middle of the cycle, most people will bump
their creatinine up to two and then come back down to their baseline.
DR.
PAZDUR: You may have a P-value there but
how does this correlate into clinical benefit and how would you envision
this? I don't really mean to revisit the
whole approval of this drug at this time.
DR.
PLUDA: Thank you.
DR.
FLEMING: Just to add to that question,
are there data in this study on differences in occurrences of fatal renal
toxicities or is there a difference in dialysis or end stage renal disease or
anything more extreme like that?
DR.
PLUDA: I don't believe there was a
difference.
DR.
PAZDUR: Obviously looking at dialysis is
an extreme situation and the medication would be stopped. In dose delays specifically because of
nephrotoxicity are dose reductions. Then
one would have to make the assumption that more is better.
CHAIR
PRZEPIORKA: But why is that important if
in fact they actually lived longer if they didn't get the stuff? To me you still come down to that ultimate point
that whatever little nuisances that you might have had to change or not change,
hey if anything I've lived longer if you didn't touch me.
DR.
PAZDUR: Here again that's the issue of
clinical benefit of the nephrotoxicity that I'm trying to eke out here.
CHAIR
PRZEPIORKA: Dr. Kelsen.
DR.
KELSEN: Following up on other patient
populations, I would be a little nervous about studying an agent that might be
a tumor protective in patients such as testicular cancer patients who are
curable. I would think you might want to
focus on a palliative population.
CHAIR
PRZEPIORKA: Does anyone from the agency
or the sponsor have any other questions for the committee?
DR.
PLUDA: I don't have any questions. I just want to thank the agency and the
committee to allow us this opportunity to get your guidance on these issues.
CHAIR
PRZEPIORKA: Thank you and let's close
the program for today and we will reconvene tomorrow at 8:00 a.m. Off the record.
(Whereupon,
at 3:46 p.m., the above-entitled matter concluded.)