1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ONCOLOGIC DRUGS ADVISORY
COMMITTEE
Hilton
2
P A R T I C I P A N T S
Committee Participants:
Bruce D. Cheson, M.D., Acting Chairman
[a.m. session]
Johanna M. Clifford, M.S., RN, BSN,
Executive
Secretary
Otis W. Brawley, M.D.
John T. Carpenter, Jr., M.D.
James H. Doroshow, M.D.
Stephen L. George, Ph.D.
Antonio J. Grillo-Lopez,
M.D.
Pamela
J. Haylock, RN
Silvana
Martino, D.O.
Gregory
H. Reaman, M.D.
Bruce G. Redman, D.O.
Maria Rodriguez, M.D.
Sarah A. Taylor, M.D.
Consultants (voting)
For Procrit:
Kenneth
Bauer, M.D.
Laurie
Feldman, Ph.D.
For CRC Endpoints:
Ronelle DuBrow, M.D.
David Kelsen, M.D., Guest Chair [p.m.
session]
Michael J. O'Connell,
M.D.
Daniel Sargent, M.D.
Patient Representatives (voting):
Nancy Roach,
FDA Participants
Clare
Gnecco, Ph.D.
Harvey
Luksenburg, M.D.
Patricia Keegan, M.D.
Karen
Weiss, M.D.
Amna
Ibrahim, M.D.
Steven
Hirschfeld, M.D., Ph.D.
Grant Williams, M.D.
Richard Pazdur, M.D.
3
C O N T E N T S
Call to Order, Introduction of Committee
- Bruce
Cheson, M.D., Acting Chair, ODAC 5
Conflict of Interest Statement - Johanna
Clifford,
M.S., RN, Executive Secretary, ODAC 8
Opening Remarks - Patricia Keegan, M.D.,
Director,
Division of Therapeutic Biological
Oncology
Products, FDA 11
Sponsor Presentations
NeoRecormon (epoetin beta) -
Hoffman-LaRoche, Ltd.,
Marty Huber
13
Johnson & Johnson, Ltd.
- Introduction - Robert DeLap, M.D.,
Ph.D., Vice
President, Global Regulatory
Affairs 26
- Evaluation of Studies - Peter Bowers,
M.D.,
Senior Director, Clinical Team Leader,
EPO, Drug
Development 33
- Future Clinical Data - Martine George,
M.D.,
Vice President, Hematology and
Oncology,
Clinical Research and Global
Development 47
Amgen, Inc.
- Introduction - Dawn Viveash, M.D., Vice
President, Regulatory Affairs and
Safety 53
- Aranesp Properties, Preclinical
Observations
and EPO Receptor Biology - Harvey
Lodish, Ph.D.,
Professor of Biology and
Bioengineering, MIT 58
- Aranesp Clinical Observations and
Pharmaco-
vigilance Program Conclusions - David
Parkinson,
M.D., Vice President, Oncology
Clinical
Development 64
FDA Presentation
Harvey Luksenburg, M.D, Medical Officer,
Division
of Therapeutic Biological Oncology
Products, FDA 84
Open Public Hearing - [NONE]
Committee Discussion 145
Lunch
213
4
C O N T E N T S
(Continued)
Introduction of Committee - David Kelsen,
M.D.,
Acting Chair, ODAC 214
Conflict of Interest Statement - Johanna
Clifford,
M.S., RN, Executive Secretary, ODAC 216
Opening Remarks - Richard Pazdur, M.D.,
Director,
Division of Oncology Drug Products,
FDA 218
Regulatory Background and Past FDA
Approvals in
Colorectal Cancer - Amna Ibrahim, M.D.,
Medical
Officer, Division of Oncology Drug
Products, FDA 225
Synopsis of FDA Colorectal Cancer Endpoints
Workshop - Michael O'Connell, M.D.,
Director,
Division of Medical Oncology, Allegheny
General
Hospital, Pittsburgh, PA 242
Disease-Free Survival (DFS) vs. Overall
Survival
(OS) as a Primary Endpoint for Adjuvant
Colon
Cancer Studies - Daniel Sargent Ph.D.,
Director,
Cancer Center Statistics, Mayo Clinic
Cancer
Center, Rochester, MN 260
Open Public Hearing 311
Committee Discussion 328
Adjourn
403
5
1 P R O C E E D I N G S
2
DR. CHESON: Good morning. Welcome to the
3
Oncologic Drug Advisory Committee, May 4th. I'm
4
Bruce Cheson from the Lombardi Comprehensive Cancer
5
Center. I am the Acting Chair of
the ODAC for
6 today's
session. I do not work for, very
clearly,
7 the
FDA in any way, shape, or form. I do
this on a
8
voluntary basis. And I am
delighted to have some
9
excellent colleagues of mine on this committee
10
today, and I would like to start off today's
11
session by having everybody at the table introduce
12
themselves, starting with my friend Antonio
13
Grillo-Lopez.
14
DR. GRILLO-LOPEZ: Thank you, Mr.
Acting
15
Chairman. My name is Antonio
Grillo-Lopez. I am a
16
hematologist/oncologist with the Neoplastic and
17
Autoimmune Diseases Research Institute.
18
MS. MAYER: I am Musa Mayer. I am the
19
patient rep for this morning's session, and I'm a
20
15-year breast cancer survivor from New York City.
21
DR. BRAWLEY: I'm Otis
Brawley. I'm a
22
medical oncologist and epidemiologist, and I'm a
6
1
professor at Emory University.
2
DR. MARTINO: Silvana Martino, medical
3
oncology, from the John Wayne Cancer Institute.
4
DR. TAYLOR: Sarah Taylor, medical
5
oncology, palliative care, University of Kansas.
6
DR. REAMAN: Gregory Reaman, pediatric
7
oncologist at the George Washington University and
8
Children's National Medical Center.
9
DR. REDMAN: Bruce Redman, medical
10
oncologist, University of Michigan.
11
MS. CLIFFORD: Johanna Clifford,
FDA,
12
Executive Secretary to this meeting.
13
DR. DOROSHOW: Jim Doroshow,
medical
14
oncologist, Director, Division of Cancer Treatment
15 and
Diagnosis, NCI.
16
DR. GEORGE: Stephen George,
Biostatistics, Duke
17 University.
18
MS. HAYLOCK: I'm Pamela
Haylock. I'm an
19
oncology nurse and doctoral student at the
20
University of Texas, Medical Branch in Galveston,
21 and
I'm the consumer representative.
22
DR. FELDMAN: Laurie Feldman. I'm a
7
1
research scientist at the Beth Israel Deaconess
2
Medical Center in Boston.
3
DR. GNECCO: Clare Gnecco. I am the
4
statistical reviewer for several of the epoetin
5
products.
6
DR. LUKSENBURG: Harvey
Luksenburg. I'm a
7
medical reviewer at the Food and Drug
8
Administration.
9
DR. KEEGAN: Patricia Keegan,
Division
10
Director, Division of Therapeutic Biological
11
Oncology Products.
12
DR. WEISS: I'm Karen Weiss,
Office of
13
Drug Evaluation VI, CDER, FDA.
14
DR. CHESON: Thank you.
15
Today we have an interesting series of
16
discussion, the morning of which will be a series
17 of
presentations and discussions concerning safety
18
concerns associated with Aranesp from Amgen and
19
Procrit from Johnson & Johnson, both of which are
20
indicated for the treatment of anemia associated
21
with cancer chemotherapy. I was
approached earlier
22 by
someone from the press who said, "How come there
8
1 has
been no buzz about this?" I think
this is
2
sufficient evidence that there is buzz about this,
3 and
I look forward to an interesting series of
4
discussions.
5
We'll start off with opening remarks from
6 Dr.
Keegan.
7
MS. CLIFFORD: Well, actually, me.
8
DR. CHESON: Oh, excuse me. From Johanna
9
first. Johanna Clifford, the
conflict of interest
10
statements.
11
MS. CLIFFORD: Thank you.
12
The following announcement addresses the
13
issue of conflict of interest with respect to this
14
meeting and is made a part of the record to
15
preclude even the appearance of such at this
16
meeting.
17
Based on the submitted agenda and
18
information provided by the participants, the
19
agency has determined that all reported interests
20 in
firms regulated by the Center for Drug
21
Evaluation and Research present no potential for a
22
conflict of interest at this meeting with the
9
1
following exceptions:
2
Dr. Maria Rodriguez has been recused from
3
participating in all matters related to the
4
discussions of safety issues associated with
5
Aranesp and Procrit.
6
Dr. Kenneth Bauer has been granted a
7
waiver under 18 U.S.C. 208(b)(3) and 21 U.S.C.
8
505(n) for owning stock in the parent company of
9 the
sponsor. The stock is valued from $5,001
to
10
$25,000.
11
Dr. John Carpenter has been
granted a
12
waiver under 18 U.S.C. 208(b)(3) for lecturing on
13 an
unrelated matter for the sponsor of Aranesp.
He
14 is
awaiting final payment of his fee that is less
15
than $5,000.
16
Dr. Otis Brawley has been granted a
17
limited waiver under 18 U.S.C. 208(b)(3) because
18 his
employer has a contract with the sponsor to
19
study Aranesp. The contract is
less than $100,000
20 a
year. Under the terms of the limited
waiver, Dr.
21
Brawley will be permitted to participate in the
22
committee's discussions; however, he will be
10
1
excluded from voting.
2
A copy of these waiver statements may be
3
obtained by submitting a written request to the
4
agency's Freedom of Information Office, Room 12A-30
5 of
the Parklawn Building.
6
Lastly, we would also like to note for the
7
record that Dr. Antonio Grillo-Lopez, Chairman,
8
Neoplastic and Autoimmune Diseases Research
9
Institute, is participating in this meeting as an
10
industry representative, acting on behalf of
11
regulated industry. He would like
to disclose that
12 he
is a scientific adviser to Chiron and receives
13
speaker fees from Wersch(ph).
14
In the event that the discussions involve
15 any
other products or firms not already on the
16
agenda for which FDA participants have a financial
17 interest,
the participants are aware of the need to
18
exclude themselves from such involvement, and their
19
exclusion will be noted for the record.
20
With respect to all other participants, we
21 ask
in the interest of fairness that they address
22 any
current or previous financial involvement with
11
1 any
firm whose product they wish to comment upon.
2
Thank you.
3
DR. CHESON: Hearing no other
comments,
4 now
we'll go to Dr. Keegan.
5
DR. KEEGAN: Thank you. I want to thank
6 the
committee and the companies who have come
7
forward to present information about the
8
erythropoietin products, both those licensed in the
9
United States and two that are not.
The purpose of
10
this is to review information based on the results
11 of
in the context of recent findings from two
12
studies from Europe that suggested that there are
13
certain practices in the administration of
14
erythropoietin products which may raise concerns
15 for
safety of the products.
16
I want to remind everyone that the
17
erythropoietin products that were approved in the
18 United
States were approved as a means of treatment
19 of
anemia in a variety of settings that, over the
20
period since original approval, there have been
21
investigations into alternative uses of these
22
products, looking at other benefits such as impact
12
1 on
survival.
2
It is in that arena that two studies
3
recently conducted in Europe identified the
4
potential for some safety concerns with those
5
particular strategies. And we
felt that it was
6
important at this time to review the available data
7
that both supported the original approval of
8
Aranesp and Procrit for treatment of anemia
9
associated with cancer, to review the clinical
10
trials in question conducted in Europe, and to
11
consider what additional information should be
12
obtained at this point in time to determine whether
13 or
not an issue would exist with Procrit or Aranesp
14 for
the treatment of anemia associated with cancer
15 and
what the design of those studies should look
16
like or to hopefully rule out any problems at the
17
labeled and recommended doses for those two
18
products. So I would ask that the
committee
19
carefully consider the data presented and provide
20 us
with some guidance in the approach of these
21
additional studies.
22
I would like to draw your attention to the
13
1
fact that there are some errors in the FDA briefing
2
document, and we have provided an errata sheet that
3
will provide corrections to those errors. In
4
addition, we have revised Question 1 of the
5 questions
to the committee in the first sentence,
6 and
the modified questions are available as an
7
errata sheet at the table outside of this room.
8
DR. CHESON: Thank you, Dr.
Keegan.
9
Since we went around the table, we've been
10
joined by another member. If you
could please
11
identify yourself and your affiliation?
Turn on
12 the
microphone, please. Hit the button.
13
DR. BAUER: Ken Bauer from
Harvard, from
14 the
VA Medical Center and Beth Israel Deaconess in
15
Boston.
16
DR. CHESON: Thank you.
17
Okay. The first presentation from
a
18
sponsor will be about NeoRecormon, or epoetin beta,
19
from Hoffman-LaRoche, Ltd. Since
I don't have your
20
name here, if you could also please introduce
21
yourself.
22
DR. HUBER: Good morning. I'm Marty
14
1
Huber, an oncologist with Hoffman-LaRoche.
2 Given the Advisory Committee's
discussion
3
today of the safety of erythropoiesis-stimulating
4
agents in the treatment of cancer patients,
5
Hoffman-LaRoche volunteered to provide data from a
6
study that was recently published in The Lancet,
7
which we'll subsequently refer to as MF4449.
8
Additionally, we'd like to provide some context for
9
these findings, reviewing some other clinical
10
trials that have been conducted with epoetin beta.
11
Just a quick background. NeoRecormon is
12 the
trade name for epoetin beta. It is a
13
recombinant human erythropoietin with a
14
well-established benefit/risk profile with more
15
than one million years of patient experience. It
16 has been available outside the United States
since
17
1990. We did not apply in the
United States for
18
approval based on patent issues.
There were no
19
safety issues which prevented it from being brought
20
into the United States. It was
not reviewed by the
21
FDA. It is approved for patients
with renal anemia
22 as
well as oncologic indications in most of these
15
1
countries.
2
For the presentation today, we'd like to
3
review MF4449 focusing initially on the primary
4
study results as published in The Lancet. We will
5
also show additional analyses that were performed
6 on
this study. We did a meta-analysis of
the
7 clinical trial data with epoetin beta, and,
8
finally, we'll look at one of our large randomized
9
studies in which we have a long-term survival
10
follow-up.
11
MF4449 was a study which was looking at an
12
investigational use of epoetin beta.
It was
13
looking at, Would increasing the hemoglobin with
14
epoetin beta lead to better efficacy of
15
radiotherapy? This was trying to
invoke
16
radiosensitization, and could that lead to improved
17
progression-free survival in cancer patients? The
18
primary endpoint was local progression-free
19
survival. For the rest of the
study, I will refer
20 to
this as PFS, or progression-free survival.
21
This is an overview of the study design.
22
Patients with head and neck cancer--and it was
16
1
males with a hemoglobin less than 13, females less
2
than 12--were randomized to receive either epoetin
3 beta, 300 international units per kilogram
sub-cu
4
three times weekly, or placebo in combination with
5
their radiotherapy. Then they
were followed up
6
until progression or another endpoint.
7
The idea was to start them two weeks
8
before the radiotherapy, but this was not done in
9 all
cases. Therefore, patients received a
total of
10
either seven to nine weeks of epoetin beta maximum.
11
Epoetin beta was not continued in the follow-up
12
period.
13
An important factor in this study was how
14 the
patients were stratified. As you know,
head
15 and
neck cancer is a very heterogeneous disease.
16
Therefore, we stratified them on the basis of tumor
17 TNM
Stage IV versus III. In addition, they
were
18
stratified by resection status.
Stratum 1 here was
19
patients who had had a complete resection. Stratum
20 2
was patients who had residual tumor after
21
resection. And Stratum 3 was,
finally, patients
22 who
received no attempt at resection and were
17
1
essentially treated with radiotherapy as their
2
primary therapy.
3
With regard to the population characs, the
4
details are in your briefing document, and they
5
were overall very well balanced.
There were a
6
couple of exceptions we'd like to point.
7
First was smoking status. This
was not
8
have a history of smoking but were they smoking at
9 the
time. We believe this is relevant
because we
10
know there is an interaction between active
11
cigarette smoking and radiotherapy which may
12
diminish the efficacy of radiotherapy.
At
13
baseline, 53 percent of patients on placebo were
14
smoking; 66 percent in the epoetin beta group.
15
Furthermore, because the patients had had
16
surgery and then were randomized, there were
17
patients who had relapsed, even prior to
18
randomization. This was in
balance, with 10
19
percent in the epoetin beta group, 7.6 percent on
20
placebo.
21
And, finally, for Stage IV TNM status,
22
there was a minimal imbalance at baseline, 72
18
1
percent versus 75 percent. But
what you will see
2 is,
as we start looking at subgroups, this
3
imbalance is magnified in an important subgroup.
4
These are the data that were shown in The
5 Lancet showing that there was a
progression-free
6
survival advantage for placebo over epoetin beta.
7
This is follow-up from--this is month six. An
8
important point here is during the first five to
9 six
months, there was no difference in
10
progression-free survival. This
will contrast with
11
some of the other data that you will review later.
12
We had conducted a series of secondary
13
analyses which were prospectively planned. The
14
intent of these analyses--we looked at the
15
robustness of the data--was: Were
the findings
16
robust throughout? And, also, was
there
17
heterogeneity in the important subgroups?
18
Furthermore, when we looked at the
19
outcome, this inferiority of epoetin beta was very
20
much unanticipated. So this was
in contrast to all
21
other clinical experience with epoetin beta. So
22
based on that, we did further additional analyses.
19
1
These were the planned secondary analyses to look
2 at
the population robustness. What I'm
showing
3
here are the Kaplan-Meiers for three populations:
4
intent to treat, radiotherapy correct, and,
5 finally,
per protocol.
6
The differences between these groups are:
7 In
the radiotherapy correct population, these are
8 the
patients who received the radiotherapy as
9
specified in the protocol. The
per protocol
10
population on the far right is not only did they
11 get
the right radiotherapy, but they also got the
12
right treatment with regards to epoetin
13
beta/placebo according to dose and schedule in the
14
protocol. The n's on this, this
is approximately
15
350, this is approximately 260, and this is around
16
220.
17
What's important to notice is that as you
18 get
to the purer population, the treatment effect
19
actually diminishes. This is
contrary to what you
20 would
expect. Normally when we do these
studies
21 for
robustness, we are looking to see the treatment
22
effect getting larger in the population that's
20
1
treated who are in per protocol.
So this indicated
2 to
us some lack of robustness in the data.
3
We did subgroup analysis. This is
a
4
forest plot. I just oriented this
slide. This is
5 the
categories, and these were categories we
6 normally
look at in head and neck trial: stratum,
7
location, staging, age, gender, smoking status, and
8
baseline hemoglobin.
9
What we looked at is, to the left is
10
outcomes better with epoetin beta, and to right is
11 better with placebo. As you can see here, there is
12 a
divergence of findings on both sides of one.
13
What we'd like to look at today is look at a couple
14 of
these subgroups in which there was the highest
15
relative risk, specifically Stratum 2 and they
16
hypopharynx.
17
Looking at the progression-free survival
18 by
stratum, this is Stratum 1, which were the
19
patients who were completely resected.
This is
20
Stratum 2, which were the patients who had residual
21
tumor. One of the things that we
found was the
22
actual progression-free survival in Stratum 2
21
1
placebo was better than placebo with completely
2
resected patients. This goes
contrary to the
3
natural history of these tumors and numerous other
4
publications. We would clearly
expect that this
5
curve should be better than this.
So what we feel
6 is
there is obviously some evidence of something
7 odd
about this placebo group.
8
Furthermore, when we looked into the tumor
9
site, if you look at the hypopharynx location,
10
there is a wide difference; there's a major
11
treatment effect. This is
placebo, epoetin beta.
12
However, all other locations there was no
13
difference in progression-free survival.
So when
14 we
do the subgroup analysis, the effect is
15
restricted to the hypopharyngeal population.
16
We looked further in this population, and
17
what we found was that we did have an imbalance
18
with regard to Stratum 3--30 percent in placebo, 45
19
percent epoetin beta--within this subgroup. These
20 are
the patients who did not have resection or
21
attempts at resection and were radiotherapy only.
22
Furthermore, we had an imbalance in the number of
22
1
patients who were in Stage IV.
2
With regards to safety, I apologize for
3
this slide. This is the
non-cancer-related adverse
4
events, but essentially they were balanced overall:
5 65
percent placebo, 68 percent epoetin beta.
6
I would like to point out one piece of
7
data here. In your briefing
document, there's a
8
reference to placebo 5 percent, epoetin beta 11
9
percent for vascular disorders.
In this
10
terminology, vascular disorders includes
11
hypertension. What we have
historically done when
12
looking at these issues, we've used the definition
13 of
thromboembolic events. It does not
include
14
hypertension. So if you see some
differences in
15
numbers, this is what accounts for it
16
When we looked at thromboembolic events,
17 we
saw placebo 3.5 percent, epoetin beta 5.6
18
percent, with some--sort of slight imbalances, with
19
more on the epoetin beta treatment group.
20
Furthermore, one of the things you may
21
have noticed in the briefing document, there was an
22
imbalance in cardiovascular deaths:
10 deaths on
23
1 the
epoetin beta group versus 5 on placebo in the
2
cardiovascular category. Given the
concerns about
3
thrombovascular events, what's important to note is
4 one
epoetin beta and one placebo occurred around
5 day
50. The remaining deaths occurred after
day
6
100. Remember, treatment was only
for a maximum of
7 seven
weeks, so these events are occurring well
8
after cessation of epoetin beta treatment.
9
In summary, we believe that there was a
10
heterogeneity of treatment effect across various
11
subgroups such as stratum, baseline hemoglobin,
12
age, gender, disease location, and that there were
13
also imbalances in important baseline
14
characteristics, smoking for the overall
15
population, as well as stage and resection status
16 for
patients with tumors in the hypopharyngeal
17
location.
18
With regards to meta-analysis, this was
19
pooled results from nine controlled clinical
20
trials, a total of 1,409 patients, with both solid
21 and
hematologic tumors. We looked at tumor
22 progression, overall survival, and
thromboembolic
24
1
events.
2
Once again this is a forest plot.
What we
3
look at is better with epoetin beta, better with
4
placebo. This is the total
population. These are
5 the
individual studies. And then this is
solid
6
versus hematologic.
7
What we saw was actually a reduction in
8
risk of progression with epoetin beta, 0.79, with a
9
difference approaching significance.
The remaining
10
studies are relatively consistent in that most of
11
them are less than 1, with a couple of exceptions,
12 but
they're very close. Also, it's a
consistent
13
finding for solid and hematologic tumors. In all
14 of
these we saw a reduced risk of progression.
15
For survival, we saw a risk of 0.97, so
16
it's essentially the same for epoetin beta and
17
placebo. And, once again, these
studies are around
18 1.
This one study, which is a higher one of 3.39,
19 if
you notice, due to the wide confident intervals.
20
Very few deaths were noted in this study.
21
We also looked at thromboembolic events in
22
this study, in this pooled study, and the control,
25
1 of
609 patients, 4 percent, epoetin beta 6 percent.
2
This was actually quite consistent with the
3
findings I presented from MF4449.
4
So, in summary, there was no
evidence of
5
increased tumor progression in patients treated
6
with epoetin beta. There was no
evidence of
7
decreased overall survival. There
was a small
8
increase in the incidence of thromboembolic events:
9 6
percent of epoetin beta versus 4 percent on
10
placebo. But what I'd like to
note is when we
11
looked at patient years of observation and
12
corrected for that, this difference disappeared.
13
The limitation of this meta-analysis is
14
most of these studies were relatively short in
15
duration because they were looking at endpoints
16
such transfusion or hemoglobin.
Therefore, we
17
looked at MF4467 to see what there a long-term
18
effect on survival. This was a
double-blind,
19
placebo-controlled study of epoetin beta in
20
patients with lymphoid malignancies.
The primary
21
endpoint was transfusion-free survival, and as you
22 can
see, there was a robust effect on that
26
1
endpoint.
2
What we did was an overall survival on
3
over 340 patients in this study.
This is the
4
Kaplan-Meier and, as you can see, there's no
5 difference
in overall survival between placebo and
6
epoetin beta.
7
In conclusion, the MF4449 study results
8 are
inconsistent with the other epoetin beta
9
studies in oncology. We believe
the most likely
10
explanation for the adverse outcomes observed in
11
MF4449 are factors independent of epoetin beta.
12 The
large majority of existing data shows that
13
epoetin beta does not adversely affect tumor
14
progression or survival in cancer patients.
15 Thank you.
16
DR. CHESON: Thank you.
17
We're going to reserve questions until
18
after the FDA makes its presentation.
19
Next, Dr. DeLap from Johnson & Johnson.
20
DR. DeLAP: Dr. Cheson, members of
the
21
panel, and guests, good morning.
I'm Dr. Robert
22
DeLap. I'm Vice President for
Regulatory Affairs
27
1 at
Johnson & Johnson Pharmaceutical Research and
2
Development, and I will be providing a brief
3
introduction to our presentation.
4
We are pleased to be able to be here today
5 to
participate in this discussion of the safety of
6
erythropoietin products in patients with cancer and
7 to
present our data in support of this discussion.
8 We
will not have time to summarize all of the
9
information that's been generated over the years in
10 our
extensive research programs, so our
11
presentation will focus on the information that we
12
deem most relevant to today's discussion. Of
13
course, we will be pleased to elaborate further on
14 any
specific points of interest.
15
Erythropoietin products are approved for
16 the
treatment of anemia associated with
17
chemotherapy.
Chemotherapy-associated anemia is a
18
common problem for patients with cancer, and this
19
anemia can be associated with debilitating symptoms
20 and
may require transfusions of red blood cells.
21
Erythropoietic products have substantial value in
22
treating anemia and its symptoms and can
28
1
significantly reduce the need for transfusions.
2
This benefits individual patients and also means
3
that the units of red blood cells that are
4
collected by blood banks can serve the needs of
5
additional patients.
6
The safety profile of erythropoietin
7
products has been well established in years of
8
clinical use, both in chemotherapy-induced anemia
9 and
in other illnesses where anemia may occur.
10
Epoetin alfa products have been the subject of may
11
clinical studies and have been used worldwide to
12 treat
more than two million patients for this
13
indication.
14
In the U.S., there are two products that
15 are
labeled for treatment of patients with cancer
16
chemotherapy-induced anemia.
These are Procrit,
17
marketed by Ortho Biotech, a J&J company, and
18
Aranesp, marketed by Amgen.
Procrit became
19
available for this indication in 1993, and Aranesp
20
became available for this indication in 2002.
21
Products available outside of the U.S.
22 include
EPREX, an epoetin alfa product that is also
29
1
marketed by J&J companies, and NeoRecormon and
2
Aranesp. All of these products
share extensive
3
homology with naturally occurring human
4
erythropoietin, and all act by binding to the
5
erythropoietin receptor with activation of
6
downstream pathways leading to red blood cell
7
production.
8
Our presentation will describe a number of
9
studies that have been done in our extensive
10
clinical research program, and we will be talking
11
about two different types of studies.
Studies in
12
supportive anemia care are the studies that were
13
used to establish the existing indication for use
14 of
these products in patients with cancer--that is,
15 the
treatment of anemia associated with cancer
16
chemotherapy. In this use, anemic
patients are
17
typically treated with a goal to obtain at least 1
18 gram per deciliter rise in hemoglobin level,
to
19
raise the patient's hemoglobin to a target range
20
that is still below normally, typically, but is
21
sufficient to reduce the likelihood of a
22
transfusion.
30
1
Beyond correction of anemia is the term
2
that we will be using today to describe
3
investigational uses that have evaluated the use
4
erythropoietin products to treat patients to higher
5
hemoglobin target levels. Recent
studies
6
evaluating the effect or erythropoietic agents on
7
cancer treatment outcomes have often utilized this
8
design.
9
It was hypothesized that any beneficial
10
effects of treatment with erythropoietic agents on
11
cancer treatment outcomes might be magnified with
12
treatment to higher hemoglobin target levels.
13
However, some of these studies have suggested
14
unexpected risks, including decreased survival.
15
This has led to extensive work that is
16
continuing at our company to better understand the
17
observations from these studies and to ensure that
18
patients and prescribers will continue to have all
19 of
the information necessary to support the safe
20 and
effective use of our erythropoietin alfa
21
products.
22
Safety data we will be presenting data are
31
1 as
follows: We will first summarize data
obtained
2 in
our clinical studies of epoetin alfa in
3
supportive anemia care, which, together with the
4
extensive clinical experience over more than a
5
decade, support the favorable risk/benefit ratio
6 for
epoetin alfa for the existing indication.
7
Second, we will summarize data from a
8
number of investigational studies that have
9
involved treatment of patients beyond correction of
10
anemia, including indications of increased risks
11
that have arisen in some of these studies using
12
that treatment approach. We
remain interested in
13
studying the effects of epoetin alfa on cancer
14
treatment outcomes, but we have modified the
15
hemoglobin target levels that we are using in that
16
research.
17
Finally, we will describe additional data
18
that we are collecting and further research that we
19
have currently under consideration.
20
We look forward to the advice of the
21
Advisory Committee today as we work to do the best
22
possible job of planning our future activities in
32
1
this area.
2
Our agenda for our presentation is as
3
follows: Dr. Peter Bowers, who
leads our clinical
4
programs with Procrit, will summarize our data from
5
epoetin alfa studies that have been done for
6
supportive anemia care and investigational studies
7
that have involved treatment beyond the correction
8 of
anemia. Dr. Martine George, who heads
our
9
entire hematology/oncology clinical development
10
program, will then describe future clinical data
11
relevant to this subject that we expect to have
12
from our currently ongoing studies and an
13
additional clinical study that we are considering
14 to
fill knowledge gaps in this area.
Finally, Dr.
15
George will conclude our presentation.
16
We have with us today several advisors to
17
help facilitate the discussion, as noted on this
18
slide, including Drs. Jesse Berlin, Kimberly
19
Blackwell, Roger Cohen, George Demitri, Mark
20
Levine, and Brian Leyland-Jones.
21
Now I would like to introduce Dr. Peter
22
Bowers for his summary of information from our
33
1
clinical study database. Thank
you.
2
DR. BOWERS: Dr. Cheson, committee
3
members, during the next minutes I will present a
4
summary of safety information available from
5
studies of epoetin alfa conducted in two settings:
6
supportive anemia care, our labeled indication, and
7
studies beyond correction of anemia.
8
We undertook a combined analysis of ten
9
completed randomized, double-blind,
10
placebo-controlled studies evaluating the use of
11
epoetin alfa, EPREX and/or Procrit, for supportive
12
anemia care. These data from
1,976 patients
13
represent all controlled studies in this setting
14 for
which we have full patient level data regarding
15
survival available. We examined
mortality hazard
16
ratios for deaths during the double-blind phase
17
plus 30 days, and also tumor response and disease
18
progression information, the latter available in
19
five of the ten studies.
Thrombotic vascular
20
event, or TVE, data from the combined analysis will
21
also be presented.
22
Some points should be kept in mind
34
1
regarding these analyses. The
studies represent a
2
variety of tumors, and many include mixed tumor
3
types. The studies were designed
and conducted to
4
assess the impact of epoetin alfa on reducing
5
transfusion and correcting anemia.
Thus, data
6
regarding survival and tumor response or disease
7
progression were collected as secondary endpoints
8
and/or for safety purposes.
Additionally, the
9
study drug treatment period ranges from 12 to 24
10
weeks, plus 4 weeks follow-up.
11
These are the results from the combined
12
analysis for mortality. The chart
in the center of
13 the
slide displays the point estimates, the red
14
dots, and the 95-percent confidence intervals, the
15
white horizontal bars. Unity is
the dashed
16
vertical line. A point estimate
less than one
17
suggests lower mortality among epoetin-treated
18
patients, and greater than one, higher mortality. This side
19 of
the chart would favor epoetin alfa;
20
this side favors placebo.
21
Please note for the combined analysis the
22
point estimate for mortality is 0.99, shown at the
35
1
bottom, with a confidence interval 0.76 to 1.28.
2
This means mortality among epoetin alfa-treated
3
patients was the same as placebo patients in these
4
studies.
5
We reviewed tumor response and disease
6
progression data from the five studies where this
7
information was collected. As you
can see,
8
response rates were similar between treatment
9
groups, and also as you see, disease progression
10
assessed in four studies was also similar between
11
treatment groups.
12
To summarize, the established benefits of
13
epoetin alfa for supportive anemia care--that is,
14
anemia related to cancer chemotherapy--include
15
transfusion reduction and amelioration of the
16
debilitating symptoms of anemia.
An evaluation of
17 the
studies in the approved indication showed no
18
signal of reduced survival and no indication of an
19
adverse impact on tumor response or disease
20
progression. Thus, the benefits
of epoetin alfa
21
therapy continue to be supported by a well-defined
22 and
acceptable risk profile when used for the
36
1
approved indication of anemia in patients receiving
2
cancer chemotherapy.
3
Now I'm going to turn to studies from
4
epoetin alfa used in settings beyond correction of
5
anemia, and before presenting the clinical data,
6 I'd
like to review very briefly some key
7
preclinical findings.
8
The preclinical literature suggests a
9
potential benefit of erythropoietins on tumor
10
growth. However, there are also
reports that
11
suggest the possibility of a deleterious effect.
12
Many tissues, including tumor cell lines, express
13
erythropoietin receptors. In
experiments by
14
Johnson & Johnson and external groups, involving
15
more than 25 different tumor cell lines, including
16
cell lines known to express erythropoietin
17
receptor, erythropoietin did not cause tumor cell
18
proliferation. Similarly,
systemic administration
19 of
epoetin at doses of 20 to 2,000 international
20
units per kilogram three times per week in in vivo
21
models of breast, lung, and ovarian cancer in vivo
22 did
not increase tumor volume. Moreover, a
37
1
positive effect on tumor growth delay has been
2
observed in animal models of concurrent
3
administration of erythropoietins in chemotherapy
4 or
radiation therapy.
5
There are conflicting reports regarding
6 the
impact of erythropoietin on tumor cell growth.
7
Some experiments in vitro indicate increased tumor
8
cell proliferation at erythropoietin concentrations
9 5-
to 100-fold greater than those achieved
10
clinically using a dose of 40,000 international
11
units.
12 Based on the balance of positive
13
preclinical data and results from Study INT-10,
14
published by Dr. Timothy Littlewood in the Journal
15 of
Clinical Oncology 2001, which suggested a
16
potential positive survival impact, the company
17
conducted Study INT-76. Details
of this trial are
18
summarized in your background briefing materials.
19
INT-76 is a large study, 939 women
20
receiving first-line chemotherapy for metastatic
21
breast cancer, with a simple design.
EPREX or
22
placebo was administered weekly and continued for
38
1 12
months, regardless of chemotherapy changes or
2
disease progression.
3
Study drug was initiated at a
hemoglobin
4 of
13 or below and titrated to maintain hemoglobin
5 in
the range 12 to 14. The primary endpoint
of the
6
study was survival at 12 months.
Objective
7
confirmation of investigator-reported secondary
8
endpoints, including disease progression and tumor
9
response, were not require. The
primary--excuse
10
me. Study drug treatment was
discontinued at the
11
recommendation of the DSMB for the study, and at
12
that time 88 percent of the subjects had completed
13
planned study drug treatment or had been withdrawn
14
from the study. The shortest
duration of treatment
15 was
nine months. Blinded follow-up continued
out
16 to
the 12-month endpoint. Groups were
generally
17
balanced with regard to prognostic factors.
18
This slide shows the Kaplan-Meier plot for
19
survival. The vertical axis is
probability of
20
survival, and the horizontal axis, time in months.
21
Below the horizontal axis are the numbers of
22
patients represented at each time point.
White is
39
1
placebo, blue represents epoetin alfa.
Please
2
observe the survival curves begin to diverge
3
relatively early in the course of follow-up such
4
that by month 4 the separation was near maximal,
5 and
the curves continued parallel out through month
6 12.
7
The primary endpoint, survival at 12
8 months,
was 24 percent survival--excuse me, deaths
9 in
the placebo group, and 30 percent deaths of
10
patients in the epoetin alfa group.
This
11
difference has a p value of 0.012.
The hazard
12
ratio for mortality at the 12-month time point was
13
1.37, the confidence interval 1.07 to 1.74.
14
In light of these unexpected results,
15
extensive analyses were undertaken by the company.
16
Post hoc analyses, including subgroup and Cox
17
modeling, were undertaken, and results of these
18
analyses should be considered exploratory and
19
interpreted cautiously. No
particular subgroup was
20
identified as accounting disproportionately for
21
most of the mortality difference.
22
Additional data were collected in a
40
1
retrospective blinded chart review of the medical
2
records of all subjects in the study.
While not
3
conclusive, the analyses in chart review, together
4
with data from other trials, provide some
5
hypotheses that might explain the observed survival
6
difference. An adverse impact of
epoetin alfa on
7
tumor proliferation is one hypothesis.
Another is
8
imbalance in fatal thrombotic vascular events. And
9
we'll look at those a little further momentarily.
10
Now, looking in detail at the cause of
11
death data we have from INT-76, investigators
12
captured cause of death on a case report form page
13
with check boxes for either disease progression or
14
other. We looked at causes of
deaths at 4 months,
15
since most of the difference in mortality had been
16
seen by that time point.
Investigators attributed
17
most deaths to disease progression with a
18
difference between the groups, as you can see on
19 the
slide.
20
In the other category, investigators
21
listed thrombotic vascular events, chemotherapy
22
toxicity, again, with differences as shown.
41
1
The blinded chart review suggested a
2
somewhat higher rate of thrombotic vascular events
3
than was reported by investigators, as you see on
4 the
bottom of the slide: two among placebo
group
5
patients, 11 among the epoetin alfa group patients,
6 at
the 4-month time point.
7
This suggests the possibility that
8
thrombotic vascular events may have been underdiagnosed or
9
-reported as a cause of death in this
10
study and may have accounted for more of the excess
11
deaths in the epoetin alfa arm than was
12
appreciated.
13
The high number of deaths within the first
14 4
months, more so in the epoetin alfa group, may
15
indicate that a more sick patient population than
16
usual for a first-line metastatic breast cancer
17
study had been enrolled. As you
can see, a greater
18
number of deaths--as you have seen, rather, a
19
greater number of deaths was attributed to disease
20
progression by investigators.
21
Further supporting the observation that
22 the
observed early differences in mortality may
42
1
have resulted in substantial part from causes other
2
than tumor proliferation, the time to disease
3
progression curves shown here--placebo, again,
4
white; epoetin alfa, blue--are superimposed.
5
Response rates for the groups are similar: 46
6
percent and 45 percent.
Thirty-eight percent of
7
patients in the placebo group developed new
8
lesions, whereas 30 percent of epoetin alfa
9
patients did. These results are
not consistent
10
with an adverse impact of epoetin alfa on tumor
11
growth.
12
Given that this is a large, randomized,
13
double-blind study with unbiased, if incomplete,
14
collection of tumor progression data, these results
15
should be considered carefully.
16
To summarize, in INT-76, an early survival
17
disadvantage was observed in the treatment group.
18
Deaths were attributed to investigators in
19
significant part to disease progression.
However,
20 investigator-reported
disease progression and
21
response rates were similar.
Given these
22
inconsistencies, other potential explanations for
43
1 the
outcome merit consideration as well and, in
2
particular, thrombotic vascular events may have
3
been underdiagnosed as a cause of death in this
4
study.
5
Now, I'd like to turn to data from other
6
studies using epoetin alfa in settings also beyond
7
correction of anemia. Here we see
summarized
8
several other studies that evaluated epoetin alfa
9 use
in these settings. These studies are
grouped
10 to
reflect status, either completed or in follow-up
11 at
the top of the chart, or discontinued in the
12
group at the bottom of the chart.
INT-76 is
13
included at the top for reference.
14
As you see, the table summarizes some key
15
details of the studies. In
general, these studies
16
have used epoetin alfa in settings where patients
17 are
not anemic or are treated to hemoglobin levels
18
that are somewhat or substantially higher than are
19
needed for correction of anemia.
20
The mortality experience is shown here.
21 For
the completed or in follow-up study, with the
22
exception of Study INT-76, mortality is not
44
1
significantly different. The five
discontinued
2
studies represent studies stopped as a result of
3
unplanned interim analyses of safety conducted at
4 the
company's request. Following this
review, more
5
than 15 studies continued, some with modifications
6 to
reduce target hemoglobins.
7
All five studies were stopped
based on an
8
unplanned analysis, and, thus, it's not possible to
9
draw definitive conclusions other than to note
10
unfavorable survival trends for epoetin
11
alfa-treated patients in some of the stopped
12
studies. Follow-up data
collection for these five
13
studies is continuing to further understand the
14
results.
15
Now, let's consider the data relevant to
16
tumor proliferation or disease response, as
17
indicated by the endpoints shown on the slide:
18
response rates, time to disease progression,
19
disease-free survival, and so forth.
20
Looking at the column on the right, the
21
differences in outcomes related to tumor response
22 or
disease progression tend to be small.
These
45
1
data show no signal that epoetin alfa is associated
2
with an adverse impact on adverse impact on tumor
3
growth.
4 Turning to clinically relevant
thrombotic
5
vascular events in this same group of studies,
6
clinically relevant thrombotic vascular events, or
7
TVEs, are those which would be regarded by
8
clinicians as significant and include both the
9
venous and arterial events, but exclude such
10
occurrences as superficial venous thrombophlebitis
11 or
catheter-related thromboses.
12
Here I've ordered the studies by frequency
13 of
clinically relevant TVEs in the epoetin
14
alfa-treated patients: 31 percent
to 1 percent.
15
Please note the substantial differences in the
16
frequency of clinically relevant TVEs.
17
Study 1015 with the greatest difference in
18 TVE
rates, 27 percent, is among the studies with
19 the
highest target hemoglobin level.
20
In contrast to this is the frequency of
21
TVEs in the ten studies of supportive care of
22
anemia. The studies are ordered
by TVE frequency
46
1 in
the epoetin alfa group, high to low, 9 percent
2 or
lower. In general, the absolute
frequency of
3
TVEs is substantially lower than is seen in the
4
group of studies beyond correction of anemia.
5
Differences between the groups are also smaller,
6
with a negative number indicating more TVEs in
7
placebo group patients.
8
Overall, the odds ratio shown at the
9
bottom of the slide is 1.55, indicating a modestly
10
increase risk of clinically relevant TVEs in the
11
epoetin alfa-treated patients, the confidence
12
interval 0.96 to 2.5.
13
In conclusion, our data indicate a
14
favorable benefit/risk profile for epoetin alfa
15
with no signal of tumor proliferation or adverse
16
survival impact in settings of supportive anemia
17
care. In study settings using
epoetin alfa beyond
18
correction of anemia, adverse outcomes have been
19
seen. However, there is no clear
signal suggesting
20 an
adverse effect on tumor proliferation.
There is
21 an
indication that thrombotic vascular events are
22
more frequent in studies with higher target
47
1
hemoglobin levels. This may
account for some,
2
possibly much, of the observed survival signal.
3
Additional data are being collected, and a
4 new
trial is under consideration. Dr.
Martine
5
George, therapeutic area head of oncology and
6
hematology at Johnson & Johnson PRD, will share
7
further details with you.
T1B DR. M. GEORGE: Thank you. 8
9
Johnson & Johnson has been studying the
10
potential benefit of epoetin alfa in the setting of
11
beyond correction of anemia since 1999, and our
12
work in this area continues.
First, I will present
13 a
clinical trial design for a study considering the
14 FDA
guidance. Then I will review with you
how
15
populated and ongoing trials could be used to
16
address the safety questions raised.
17
We considered several clinical trial
18
designs according to the agency requests, and after
19
critical analysis, we decided to select advanced
20
breast cancer. Our proposed
clinical trial will
21
focus on breast cancer based on the signal observed
22 in
INT-76, on the EPO receptor presence on breast
48
1
tumor, which is well known, on the high incidence
2 of
the disease in the population, and also based on
3 the
need for homogeneity in terms of patient
4
population and chemotherapy.
5
Furthermore, early clinical trials in
6
anemic patients have suggested a favorable outcome
7 in
patients with anemia treated with erythropoietin. The
8
unfavorable outcome of INT-76 doesn't
9
preclude a potential benefit in anemic patients.
10 We are assuming a potential benefit,
but
11 the
trial will have to be powered to exclude a
12
negative effect, as requested by the agency.
13
The objective of the trial is simple.
14
It's to evaluate the effects of EPO alfa on cancer
15
outcomes in patients with metastatic breast cancer
16
receiving first-line chemotherapy.
17
The proposed clinical trial will be
18
double-blind, randomized, placebo-controlled, and
19
will enroll patients with advanced breast cancer
20
receiving first-line chemotherapy, including taxane
21
and/or anthracyclines. Patients
will be anemic at
22
entry with hemoglobin at baseline equal to or less
49
1
than 11 grams per deciliter before their third
2
cycle of chemotherapy. Patients
will receive EPREX
3 or
placebo until tumor progression, end of
4
chemotherapy, or death. The
target hemoglobin
5
level in the study will be 12 grams per deciliter,
6 and
we'll hold the drug if the hemoglobin goes over
7 13
grams per deciliter.
8
The endpoints of the clinical trial will
9 be
as follows: The primary endpoint will be
10
progression-free survival, and because of lack of
11
time, I won't expand on how we are going to assess
12
progression-free survival.
Secondary endpoints
13
will include overall survival, thrombotic vascular
14
events, response rate, and TTP.
15
Statistical methods will
include a
16
non-inferiority comparison, possibly followed by a
17
superiority test. Two thousand
patients will
18
provide 80-percent power to exclude a 15-percent
19
reduction in progression-free survival, assuming no
20
difference. If non-inferiority is
demonstrated, a
21
superiority test will be done.
There will be
22
80-percent power to detect a 15-percent gain in
50
1
progression-free survival.
2
There are some considerations when
3
designing the trial in which we will particularly
4
welcome your feedback. The first
challenge is to
5 run
a placebo-controlled trial when anemic patients
6 receive
drug treatment as a standard of care.
7
Crossover of placebo patients following the
8
double-blind phase could obscure the assessment of
9
overall survival.
10
Second, functionality of the EPO receptor
11 is
best addressed in fresh frozen samples.
12
Collecting samples may significantly slow down
13
patient enrollment into the trial and would delay
14
study completion. However, more
preclinical
15
studies to assess ligand affinity, signal
16
transduction, and gene expression are warranted to
17
better understand the receptor and its
18
functionality.
19
Providing patients with a homogenous
20
chemotherapy regimen is complicated, but at least
21
three elements: the previous
adjuvant
22
chemotherapy, the wide range of available
51
1
therapies, and constant innovation in therapy.
2
And, finally, this clinical trial should
3 provide
an opportunity to better understand and
4
control the causes of thrombotic events.
5
In the next two to three years, as
6
depicted on the slide, we will have considerably
7
more information in the areas of tumor control and
8
survival from the tumor types where we have
9
observed a survival signal:
breast cancer, head
10 and
neck cancer, lung cancer, as well as some more
11
data in carcinoma of the cervix, all in studies
12
beyond the correction of anemia.
13
In summary, we will have a significant
14
amount of additional data in the next two to three
15
years from those recently completed studies and
16
ongoing studies. This data will
provide
17
significant information in various tumor types.
18
We welcome your advice and opinions on the
19
timing, design, and challenges of the proposed
20
study.
21
And now I would like to conclude the
22
Johnson & Johnson presentation.
As you have read,
52
1
seen, and heard, in the supportive care of anemia
2 we
have extensive clinical experience which
3
supports the favorable benefit/risk profile of
4
Procrit. We take very seriously
the survival
5
signal observed in metastatic breast cancer and
6
head and neck cancer that occurred in studies
7
assessing the benefit beyond the correction of
8
anemia with two different products:
EPREX and
9
NeoRecormon. We have looked for
and found no clear
10
tumor proliferation signal as assessed by response
11
rate and tumor progression.
12
We note that TVEs account for some,
13
potentially much, of the negative signal we have
14
observed in those trials. In
contrast, some
15
studies in supportive anemia suggest a potential
16
benefit in cancer outcome, and future clinical
17
evaluation in that setting may provide the answer
18 to
that question.
19
In summary, Procrit provides
important
20
benefits for patients with cancer by decreasing
21
transfusion and alleviating anemia symptoms. We
22 are
committed to maximizing those benefits and
53
1
minimizing the risks associated with its use.
2
We look forward to working with ODAC and
3 FDA
to optimize our current and future development
4
programs.
5
Thank you very much for your attention.
6
DR. CHESON: Now we will move on
to the
7
Amgen presentations, their partners for the day.
8
Dawn Viveash will do the introductions.
9
DR. VIVEASH: Good morning,
members of the
10
committee, FDA participants, ladies and gentlemen.
11
Amgen is pleased to be here today to present data
12
regarding the benefit and safety of Aranesp in the
13
treatment of patients with chemotherapy-induced
14
anemia.
15
We have with us today a number of
16
distinguished guests: Dr. Jeffrey
Crawford, Dr.
17
David DeMets, Dr. John Glaspy, Dr. Harvey Lodish,
18 Dr.
Douglas Losordo, Dr. Marc Pfeffer, and Dr.
19
Joseph Eschbach.
20
In addition, we have a number of
21
independent investigators who are currently
22
conducting oncology studies with Aranesp. These
54
1
investigators are Dr. Overgaard, representing the
2
Danish Head and Neck Cancer Study Group; Directors.
3
Delarue and Bosley, representing the GELA Lymphoma
4
Study Group; Dr. Nitz, representing the West German
5
study; and Dr. Kahlert, representing the German
6
Gynecological Oncology Study Group.
7 I will open the presentation with a
brief
8
overview on preclinical and clinical properties of
9
Aranesp. There has been a change
on our agenda.
10 As
you'll see, we have a different cast of
11
presenters than is shown on the published agenda.
12 We
will have Dr. Harvey Lodish discuss considerations
13
regarding the epoetin receptor.
His lab was
14 the
first to clone the EPO receptor. He is
15
professor of biology and bioengineering at MIT and
16 is
a member of the National Academy of Science.
17 Dr.
David Parkinson will describe the clinical
18
observations with Aranesp, and he will also provide
19 an
overview of our clinical trial program.
20
Aranesp is a distinct erythropoietic
21
molecule. The development of
Aranesp represents
22 the
combination of over ten years of research
55
1
during which time more than 450 molecules were
2
characterized. Aranesp is unique
as a result of
3 its
novel amino acid sequence, which allows for two
4
additional carbohydrate chains, leading to an
5
increased negative charge and increase in molecular
6
weight. The terminal half-life of
Aranesp is
7
three-fold greater than epoetin, and because of its
8
longer half-life less frequent dosing can be
9
utilized compared to erythropoietin.
10
Aranesp was initially approved in 2001 for
11 the
treatment of anemia associated with chronic
12
renal failure in both dialysis and non-dialysis
13
patients. It was subsequently
approved in July of
14
2002 for chemotherapy-induced anemia.
15
I'd like to highlight some relevant safety
16
information from the package insert.
The warnings
17
section represents prior observations from the
18
Normal Hematocrit Study which was conducted with
19
EPOGEN. This was conducted in
dialysis patients
20
with pre-existing cardiovascular disease. This
21
section also addresses high hemoglobin, rate of
22
rise, and mortality.
56
1
The dosing guidance recommends a
2
hemoglobin target of 12 and provides instructions
3 for
dosage adjustment to avoid excessive rate of
4
rise of hemoglobin.
5
The precautions section includes a
6
statement regarding the theoretical concern of
7
growth factor potential, and the adverse reactions
8 section describes the thrombovascular events.
9
You are now well aware of the findings
10
from studies with epoetin alfa and epoetin beta and
11
their observations regarding survival, tumor
12
progression, and thrombotic events.
When Amgen
13
became aware of these findings, we conducted a
14
comprehensive review of preclinical and clinical
15
data.
16
The preclinical data with respect to
17
Aranesp does not support the contention that this
18 agent
stimulates tumor growth. Aranesp is not
19
genotoxic. There were not
proliferative or
20
hyperplastic signals in six-month toxicology
21
studies. In addition, there was
no off-target
22
binding of Aranesp, and no off-target effects were
57
1
seen with Aranesp or erythropoietin in toxicology
2
studies.
3
In studies of tumor xenografts, one of
4
which was performed by Dr. Blackwell from Duke
5
University, who is present here today, there was no
6
stimulation of tumor proliferation.
In fact, to
7 the
contrary, there was a potential beneficial
8
effect observed when Aranesp was administered in
9
combination with radiotherapy in some models.
10
The clinical review includes
11
epidemiological analysis of thrombotic events and a
12
review of completed and ongoing Aranesp trials and
13
also an assessment of post-marketing experience.
14 Dr.
Parkinson will review our observations from the
15
clinical data.
16
Based on this comprehensive review of
17
oncology data, we did not identify any adverse
18
survival or tumor progression signal with Aranesp.
19 The
thrombotic event rate remains consistent with
20
that represented in the product label.
21
One of the hypotheses that has been put
22
forward from the signals observed in the BEST and
58
1
Enhanced studies relates to the role of the EPO
2
receptor in tumor progression. I
would like to ask
3 Dr.
Lodish to address the potential relevance of
4 the
EPO receptor on tumors and the utility of
5
current methods to detect the receptor.
6
Thank you, Dr. Lodish.
7
DR. LODISH: Thank you.
8
To begin, I'd like to emphasize that mere
9
detection of the EPO receptor on tumor cells--or
10
normal cells, for that matter--does not mean that
11
erythropoietic agents drive the oncogenic process.
12 The
EPO receptor is present at very low levels on
13
many normal and tumor cells, but the EPO receptor
14
does not possess any of the characteristics of an
15 oncogenic receptor.
16
For example, as you know, established
17
oncogenic tyrosine kinase receptors, such as HER2
18 or
the epidermal growth factor receptor, are
19
amplified and mutated in many types of human
20
tumors. Receptors can be
overexpressed as many as
21
100,000 or a million copies per cell in certain
22
cancers. In other cases, mutation
leads to
59
1
constituitive--that is, hormone
2 independent--activation. Both cases are
3
transforming, are prognostic markers, and are
4
established therapeutic targets.
5
The situation is quite different for the
6 EPO
receptor. With the sole exception of
erythroleukemia,
7
where EPO gene amplification has been
8
recognized, EPO receptor amplification has not been
9
seen in human tumors. The
presence of gene
10
amplification into erythroleukemic cell lines
11
illustrates that the failure to detect involvement
12 of
the EPO receptor in the vast majority of cancer
13
samples is genuine and not simply a false negative
14
result. And it's my understanding
that Aranesp
15
treatment of erythroleukemia is not recommended.
16
Importantly, there are no
constituitive
17
reactive--that is, hormone independent--EPO
18
receptor mutants in any human or animal tumors.
19 The
one case of humans with mutations in the EPO
20
receptor involve truncations of the cytoplasmic
21
domain that render the receptors hypersensitive to
22
erythropoietin. These individuals
develop
60
1
polycythemia but have no increased tumor incidence.
2
And, in conclusion, then, the
EPO receptor
3 is
not known to initiate tumorigenicity or cause
4
primary solid tumors to proliferate.
There are no
5
known correlations of EPO receptor expression or
6
mutation with any aspect of oncogenicity.
7
I've also been asked to comment on
8
methodological aspects of existing and potential
9
assays for functional EPO receptors on primary
10
solid tumors. And before doing
that, I'd like to
11
point out several important aspects of EPO receptor
12
expression on erythroid cells.
13
First of all, over 90 percent, well over
14 90
percent of the EPO receptors in erythroid cells
15 are
not on the cell surface. They're in the
16
cytoplasm on various membranes.
Erythroid cells
17
have only 1,000 to 2,000 receptors on their
18
surface. Non-erythroid cells are
transformed or
19
otherwise generally have much less.
And,
20
importantly, surface expression of the receptor
21 requires
expression of the JAK-2 protein tyrosine
22
kinase and possibly other accessory proteins.
61
1
Finally, the high-affinity receptor that
2 is
seen on erythroid cells, the signaling receptor,
3
forms a one-erythropoietin, 2-receptor complex that
4
initiates downstream signaling.
The low-affinity
5
receptors that are seen on the vast majority of
6
normal and tumor cells are low-affinity, as I said,
7 and
likely are forming a 1-erythropoietin,
8
1-erythropoietin complex and are not signaling.
9
Concerning the assays that one might think
10 of
for erythropoietin receptor detection in primary
11
tumors, I'd like to point out several points.
12
First of all, numerous publications discuss EPO
13
receptor expression and function in tumor cell
14
lines, but it's not clear that these translate to
15
primary tumor samples in a clinical setting. And,
16
importantly, only cell surface receptors are
17
clinically and biologically relevant.
Only these
18
receptors can bind to erythropoietin and send
19
signals to the inside of the cell.
20
It's important to note that there are no
21
measurements for functional epoetin receptors
22
possible in fixed or frozen tissues.
Reverse
62
1
transcriptase polymerase chain reaction, RT-PCR,
2
measures RNA copies or transcripts of the EPO
3
receptor gene. That does not
necessarily measure
4
functional EPO receptor message and does not
5
measure EPO receptor protein, and certainly not
6
functional receptor. And,
importantly, these
7 studies
would require separation of the tumor cells
8
from the other cells in the tumor.
9
Immunohistochemistry measures erythropoietin
10
receptors in the cytoplasm and is too
11
insensitive to detect the minute numbers that might
12 be
expected on the surface of cells. And,
13
importantly, the existing antibodies, commercial or
14
otherwise, are simply not sufficiently specific to
15
detect EPO receptors among other background
16
proteins.
17
There are ways of detecting functional EPO
18
receptors in fresh tumor biopsies, but they also
19
present many problems. First of
all, these
20
measurements would require fresh samples of cells
21 and
samples in which the tumor cells have been
22
separate from the non-tumor cells.
Binding with
63
1
radiolabeled EPO to cell surface receptors is
2
possible, but it is very difficult to detect the
3 low
numbers of low-affinity receptors--and by low
4
numbers, I mean under 1,000 receptors--present in
5
cells. And it's difficult to
resolve the specific
6
saturable binding to cell surface EPO receptors
7
from the non-specific, non-saturable binding to
8
other cell surface components.
9
Proliferation of tumor cells in culture
10 and
response to EPO is also not practical for the
11
simple reason that, as you know, fresh tumor cells
12
generally are not viable in culture.
In my view,
13 the
only assay that would detect functional EPO
14
receptors in tumor cells--or, for that matter,
15
other types of cells--involve EPO-induced
16
activation of downstream signaling proteins as
17
measured by, say, phosphorylation of the
18
erythropoietin receptor, the JAK-2 kinase, other
19
signaling proteins. These are
complicated assays
20
that require, as do the others, on the order of ten
21
million cells per assay. The
cells, again, must
22
have been purified from other cells, and in
64
1
non-erythroid cells, these immuno-precipitation
2
Western blot analyses are quite insensitive and
3
have a very low signal-to-background ratio.
4
So, in conclusion, there are no presently
5
available assays suitable for routine measurement
6 of
functional erythropoietin receptors on primary
7
solid human tumors. Development
of such assays
8 will take years, and it's unclear to me what
form
9
these assays might ultimately take.
10
I now turn the podium over to Dr.
11
Parkinson, who will discuss the clinical
12
observations.
13
DR. PARKINSON: Good morning. Thank you,
14 Dr.
Lodish.
15
Outlined are the clinical observations
16
which I will discuss relevant to this morning's
17
meeting. After briefly reviewing
some of the
18
benefits associated with the treatment of anemia,
19
I'll present the results of Amgen's studies of the
20
risk of thrombotic events in association with
21
erythropoietins. Next I'll
present the analysis of
22
survival in completed clinical trials.
And,
65
1
finally, I'll outline a program of ongoing trials
2
involving Aranesp in different tumor treatment
3
settings.
4
Together, these trials have power to
5
detect a safety signal far smaller than those which
6
have been discussed already this morning. We
7
believe this represents a responsible and credible
8
approach to definitively resolving the questions
9
raise in this morning's meeting.
10
With regard to the cancer indication,
11
today we're here primarily to consider risks. But
12 no
meaningful discussion of risk can occur in the
13
absence of a consideration of benefit.
Anemia,
14
which translates in patients with cancer into the
15
important symptom of fatigue, is a highly prevalent
16
comorbidity which significantly affects the quality
17 of
life in patients with cancer. Without
18
erythropoietic protein therapy, 90 percent of
19
cancer patients undergoing chemotherapy will have
20
some level of anemia, and some 40 to 60 percent of
21
those patients will require transfusions.
22
Historically, chemotherapy-related anemia
66
1 has
been treated with transfusion, with its
2
attendant inconveniences and risks.
Not only is
3
fatigue common in cancer patients, but fatigue as a
4
symptom is rated by the majority of patients to be
5
more important even than pain.
6
The left side of this panel shows the
7
hematopoietic response indication correction of
8
anemia by Aranesp therapy.
Portrayed to the right
9 is
the significant decrease in the rate of
10
transfusion with Aranesp therapy utilizing dosing
11
intervals extending as far as three weeks.
12
Extensive literature suggests the
13
association of this anemia correction with improved
14
fatigue and other quality-of-life scores.
15
Recognition by the oncology community of the
16
importance of anemia and the benefits of its
17
treatment with erythropoietic proteins have led to
18 the
production of independent, evidence-based
19
treatment guidelines. These
include treatment
20 algorithms
and desirable upper levels for
21
hemoglobin.
22
These evidence-based guidelines have been
67
1
incorporated by Amgen into our current trials and
2 analyses. Furthermore, treatment recommendations
3 in
the product label are consistent with these
4
guidelines.
5
We'll now present the results of our
6
evaluation of thrombotic events in patients with
7
cancer. First of all, it's well
established that
8
patients with cancer have a higher background rate
9 of
thrombotic events. A full description of
the
10
epidemiology of these events in patients with
11
cancer is outlined in our briefing document. We
12
have extensively reviewed that.
13
The increased risk of thrombotic events
14
with Aranesp therapy is represented in the adverse
15
events section of the Aranesp label, as has already
16
been discussed by Dr. Viveash.
But we proactively
17
initiated a reevaluation of thrombotic event
18
experience within Aranesp clinical trials--these
19 are
11 completed trials as of late last
20
year--involving more than 1,800 Aranesp-treated
21
subjects relative to more than 400 placebo-treated
22
subjects.
68
1
On this slide, we see that our own Amgen
2
analysis of the Medstat Claims database reflecting
3
patients treated primarily with erythropoietin alfa
4
also shows an increased risk of thrombotic events
5
with epoetin alfa therapy. This
analysis is
6
consistent with the Cochran meta-analysis involving
7
cancer patients receiving either erythropoietin
8 alfa or beta, presented by Bohlius, et al.,
at the
9
December American Society of Hematology meeting,
10 the
relative risks of thrombotic events in our
11
study and the Bohlius study being 1.4 and 1.55,
12
respectively.
13
We'll now show you our analysis
of
14
survival in completed clinical trials.
15
We identified four suitable randomized,
16
double-blind, placebo-controlled trials.
Two of
17
these, involving more than 600 patients, had
18 long-term
follow-up and with 360 events allow us to
19
carefully evaluate Aranesp's effect on survival.
20 One
trial was conducted in lung cancer and included
21
anemic patients beginning platinum-based
22
chemotherapy. A second trial involved
patients
69
1
with five different lymphoid malignancies. In this
2
trial, Aranesp therapy was initiated when patients
3
became anemic. Finally, Amgen
conducted a pooled
4
analysis involving these two trials and two
5
additional controlled trials comprising more
6
heterogeneous patient populations.
7
The first of the studies, in lung cancer,
8 is
represented on this slide. More than 300
9
patients with either small-cell or non-small-cell
10
lung cancer beginning platinum-based chemotherapy
11
were randomized to weekly Aranesp or placebo. The
12
relatively homogeneous patient population, the fact
13
that most patients were beginning chemotherapy, and
14 the
long-term follow-up make the study very
15
appropriate for survival analysis.
Seventy percent
16 of
these patients have been followed until death.
17
On this slide, we see the results of this
18
study in lung cancer. There is no
evidence of any
19
decrease in progression-free survival with Aranesp.
20 In
the Amgen briefing document, we've provided a
21
breakdown of small-cell and non-small-cell lung
22
cancer subjects. These subsets
behave similarly.
70
1
This slide shows similar results for
2
overall survival. The sample size
of the trial and
3 the
number of observed deaths were appropriate to
4
detect reduced survival of the magnitude seen in
5 the
BEST and Enhanced or Henke trials. Yet
there
6 is
evidence for any negative survival influence
7
with Aranesp therapy.
8
Trial 161, this lymphoid malignancy trial,
9
differs from the lung cancer trial, as I've
10
indicated, since patients with multiple lymphoid
11
tumor types were eligible, and these patients could
12 be
randomized anytime during the course of
13
chemotherapy. In this study, 344
patients with one
14 of
five different lymphoid malignancies with
15
chemotherapy-induced anemia were randomized to
16
receive either weekly Aranesp or placebo. The
17
distribution of the different malignancies is
18
outlined here.
19
The slide illustrates the baseline
20
characteristics of the patients in the lymphoid
21
malignancy trial. The study,
while it did include
22
long-term follow-up, was again designed to study
71
1
anemia. As a consequence,
patients were not
2
stratified for malignancy-specific prognostic
3
factors. This led by chance, as
you can see, to
4
patients with the worse prognosis for both
5
non-Hodgkin's lymphoma and chronic lymphocytic
6
leukemia to be assigned to the Aranesp arm.
7
This slide indicates the trial result.
We
8 see
on this slide no evidence for a significant
9
decrease in progression-free survival.
The hazard
10
ratio, which is adjusted for disease type, stage,
11 and
IPI score, is greater than 1 but the confidence
12
interval extends below 1. We
continue to follow
13
these patients.
14
On this slide, we observe no convincing
15
evidence for a significant decrease in overall
16
survival in association with Aranesp therapy.
17
Again, the hazard ratio is above 1, but the
18
confidence interval extends below 1.
We've
19
presented data on individual lymphoid malignancy
20
subset in the briefing document.
21
I will now review the pooled analyses for
22
these completed trials.
72
1
As previously noted, two other randomized,
2
double-blind, placebo-controlled short trials with
3
short-term follow-up were considered to be
4
appropriate for the pooled analysis and to
5
contribute particularly to the study of the early
6 part of the survival curve which seemed to
be so
7
important in the BEST trial results, as you've
8
heard.
9
On this slide are demonstrated the number
10 of
patients and the breakdown by tumor type of the
11
patients contributing to this pooled analysis with
12
cumulative follow-up involved.
Combined, these
13
trials provide more than a 80-percent power to
14
detect an effect on survival of the magnitude seen
15 in
the BEST and Enhanced trials.
16 I'll now review results starting with
17
progression-free survival.
18
Portrayed here is the progression-free
19
survival in the overall pooled analysis.
Note here
20
that the time scale extends to 16 weeks and that
21 the
progression-free survival percent extends from
22 80
to 100. We've magnified the scale. The hazard
73
1
ratio is close to 1, and there is no evidence of an
2
effect of Aranesp on progression-free survival
3
during this period.
4
On this slide, we again see no evidence
5 for
a negative overall survival influence in
6
association with Aranesp therapy.
In addition, as
7
shown in our briefing document, the long-term
8
follow-up from this pooled data set is a hazard
9
ratio of approximately 1. The
confidence interval
10 for
that analysis extends from 0.8 to 1.2, which
11
excludes an effect of the size seen in the BEST and
12
Enhanced trials.
13
I will now review the analysis by tumor
14
type.
15
On this slide, I portray the
16
progression-free survival results of the pooled
17
analysis by tumor type. No clear
association is
18
observed between progression-free survival and
19
tumor type. Results are similar
with respect to
20
overall survival.
21
Here we find an association with improved
22
progression-free survival and overall survival is
74
1
observed with respect to achieving an on-study rise
2 in
hemoglobin of 1 gram per deciliter or more over
3 14
days. These hazard ratios are 0.51 and
0.43,
4
respectively, with the indicated confidence
5
intervals.
6
Note that a similar association is found
7
with improved progression-free survival and overall
8
survival with respect to achieving an on-study
9
hemoglobin of greater than or equal to 13 grams per
10
deciliter.
11
In summary, our more recent analyses have
12
confirmed the appropriateness of the Aranesp
13
prescribing information with respect to thrombotic
14
event rate. In an evaluation of
data from over
15
1,100 patients randomized to placebo-controlled
16
oncology trials with Aranesp, we found nearly
17
identical survival and progression-free survival
18
with Aranesp and placebo. We
believe that our
19
detailed examination confirms the safety profile of
20
Aranesp and that the benefit/risk ratio remains
21
favorable and warrants continued examination of
22
potential beneficial effects on survival.
75
1
I will now review a program of ongoing
2
trials involving Aranesp in different tumor
3
treatment settings. We believe
this group of
4
trials represents a robust approach to ultimately
5
resolving the questions raised in this meeting.
6 The
trials to be described were initiated, I should
7
point out, because of evidence regarding the
8
positive potential benefits of anemia treatment on
9
patient survival. Outlined here
are the relevant
10
preclinical and clinical observations providing the
11
rationale for these trials.
12
On particular note at the bottom is the
13
Cochran meta-analysis with a favorable relative
14
risk and a conclusion by the authors that more
15 trials
to explore this finding were merited.
16
On the next several slides are outlined
17 the
Amgen-sponsored and the four independent
18
investigator-initiated and
-conducted studies.
19 The
Amgen response to the information from the BEST
20 and
Enhanced trials has already been described by
21 Dr.
Viveash, including our formal review of all
22
ongoing clinical trials involving Aranesp being
76
1 conducted
worldwide.
2
One of our goals in this review was to
3
identify clinical trials in which the design, the
4
size, and the patient population would be
5
particularly informative with respect to answering
6 the
kinds of questions that we're dealing with
7
today. We identified five such
trials--one
8
Amgen-sponsored and four utilizing Aranesp but
9
being conducted by independent investigators. All
10 of
these studies are randomized and controlled.
11 One
trial is itself double-blind and
12
placebo-controlled. The other
four clinical trials
13
involve randomization to Aranesp or no epoetin. In
14
these trials, Aranesp treatment is administered
15
proximate to the time of chemotherapy and not for
16 the
full duration of follow-up. These
studies
17
include long-term follow-up with collection of
18
predefined progression and survival endpoints. In
19
addition, of course, the studies will capture
20
thrombotic and cardiovascular events.
Each study
21
includes homogeneous populations with
22
stratification for disease-specific prognostic
77
1
variables.
2
One question posed by the FDA relates to
3 the
feasibility and appropriateness of conducting
4
placebo-controlled studies. You
will note that, as
5
I've indicated, one of our studies includes
6
placebo-controlled design. While
these studies are
7
currently ongoing in Europe, we can report that we
8 are
successfully accruing patients to a
9
placebo-controlled trial of Aranesp in
10
chemotherapy-induced anemia in the United States if
11
that's relevant to your deliberations.
12
In fact, it is our opinion that controlled
13
studies are essential in certain situations and
14
that it is feasible to conduct such studies in the
15
United States.
16
On this slide, we also indicate that the
17 number of patients for each tumor type and the
18
total number of patients for these five trials
19
being over 3,500. We believe that
there is
20
particular value to an approach which incorporates
21 a
range of tumors with robust numbers of patients
22 in
both breast cancer and head and neck cancer.
I
78
1
will now review each study design in detail.
2
Portrayed here is the Amgen-sponsored,
3 double-blind,
placebo-controlled study. Six
4
hundred patients with newly diagnosed extensive
5
small-cell lung cancer will be randomized to
6
combination chemotherapy with Aranesp or placebo.
7 As
you can see, endpoints include survival, and
8
this trial has accrued more than 200 patients to
9
date. I'd like to point out again
that this trial
10 is
placebo-controlled.
11
The first independent
12
investigator-conducted trial which I will discuss
13 is
the neoadjuvant breast cancer trial being
14
conducted by the German Gynecologic Oncology Group.
15
Seven hundred patients with diagnosed breast cancer
16
will be randomized to dose-intense or standard
17
chemotherapy with a secondary randomization to
18
Aranesp or observation. Following
induction
19
chemotherapy, surgery will be conducted.
Endpoints
20 are
as listed; follow-up is long term.
21
By the nature of this patient population
22 and
by the nature of the study design and
79
1
investigator intent with Amgen support, tumor
2
tissue is being collected and stored.
The trial
3 has
accrued more than 400 patients, half of the
4
projected total accrual. An
interim analysis of
5 the
experience in the first 200 patients will take
6
place in the next several weeks.
7
The second investigator-initiated study is
8 the
adjuvant breast cancer study being conducted by
9 the
West German Study Group. After
definitive
10
surgery, the projected 1,000 patients will be
11
randomized to center-specific adjuvant chemotherapy
12
with or without Aranesp.
Endpoints are as listed,
13 and
this trial has recently initiated accrual.
14
The diffuse large-cell lymphoma study
15
conducted by the French, Belgian, and Swiss GELA,
16 is
outlined here. More than 600 patients
will be
17
randomized to 14- or 21-day monoclonal antibody
18
CHOP(?) chemotherapy treatment regimens.
These
19
patients are secondarily randomized to Aranesp or
20
supportive transfusion. Endpoints
are as listed;
21
long-term follow-up is involved.
This trial has
22
recently initiated accrual.
80
1
The head and neck cancer study being
2
conducted by the Danish Head and Neck Cancer Study
3
Group is outlined here to test the hypothesis that
4 anemia contributes to radiotherapy
failure. A
5
projected 600 patients with head and neck cancer
6 are
randomized to radiotherapy alone or to Aranesp
7
with long-term follow-up. The
principal
8
investigator is Professor Overgaard, a
9
well-recognized authority in the field of tumor
10
oxygenation and radiation therapy.
More than 260
11
patients have already been accrued to this trial.
12
In response to the Henke and Enhanced
13
trial results, the investigators have conducted an
14
interim analysis for safety. We
are informed that
15
this trial is proceeding.
16
On this slide, the five clinical trials
17 are
outlined with respect to the tumor types
18
involves, projected and current accrual, and the
19
detectable differences from the expected control
20 arm
results. Individually, these trials will
21
accrue between 600 and 1,000 patients and have
22
power to detect absolute differences in survival
81
1
between 7 and 11 percent. Note
that these studies
2 are
ongoing outside of the United States, but we
3
believe the findings should absolutely be
4
applicable to United States practice.
5
This slide shows the statistical power of
6 the
individual trials to detect an increase in the
7
risk of death. Each of these
trials has reasonable
8
power to detect a hazard ratio of 1.4 or 1.5. Even
9 if the
true hazard ratio is as low as 1.2, there is
10 a
greater than 85-percent chance that at least one
11 of
these trials will result in a statistically
12
significant difference.
13
On this slide is outlined the projected
14 accrual
over time to these trials and the expected
15
cumulative patient years of follow-up.
Including
16 all
five ongoing studies, more than 3,500 patients
17
will be randomized in trial settings in which the
18
influence of Aranesp on survival can be compared.
19
This slide shows the power of a
20
meta-analysis illustrated in yellow of all five
21
trials. This analysis will have
high power to
22
detect a true hazard ratio as small as 1.15, which
82
1 is
far smaller than that observed in the BEST and
2
Enhanced trials.
3
Also shown on this graph in the purple is
4 the
power of the meta-analysis of the neoadjuvant
5 and
adjuvant breast cancer studies, a total of
6
1,700 breast cancer patients.
This analysis will
7
have 80-percent power to detect a true hazard ratio
8 as
small as 1.32.
9
So on this slide, I've summarized the
10
strengths of the ongoing clinical trials
11
activities. As I've discussed,
these include
12
design elements which involve either double-blind,
13
placebo-controlled, or Aranesp versus epoetin
14
elements, with predefined survival or tumor
15
progression endpoints. I'd like
to emphasize this
16 in
view of the agency's first question.
17
While it is true that these trials are all
18
being conducted ex-U.S., we would point out that it
19 is
entirely possible to conduct placebo-controlled
20
trials in the United States.
These ongoing trials
21
cross multiple tumor types with approximately 1,700
22
breast cancer patients and 600 head and neck cancer
83
1
patients. The cumulative
meta-analyses of 3,500
2
patients will provide robust power for assessment
3 of
survival outcomes in this program.
4
Of note, these studies have already
5
accrued close to 900 patients.
These studies
6
include careful safety monitoring, and the AGO
7
breast cancer trial incorporates tissue collection
8 to
enable appropriate correlative biological
9
studies.
10
In conclusion, we've outlined the known
11 and
potential benefits of therapy with Aranesp.
We
12
have found no adverse effects on tumor progression
13 or
survival to date in our Aranesp clinical trials.
14 To
the contrary, evidence exists for potential
15
benefit from erythropoietic protein therapy, both
16 in
the settings of cancer and other conditions.
17
It is our position that this potential
18
benefit should be studies, but that such studies
19
must be carried out responsibly, with carefully
20
designed and executed trials.
21
Thank you very much.
T2A DR. CHESON: I would like to thank the
22
84
1
sponsors for their very clear and on-time
2
presentations.
3
And now I'd like to turn to the FDA
4
presentation, Dr. Harvey Luksenburg--who is going
5 out
the door.
6
[Laughter.]
7
DR. CHESON: Harvey, come back,
please.
8 And
for those of you who are standing against the
9
side wall, if you would please, for fire safety
10
reasons, stand in the back or you'll have to be
11
asked to leave the room.
12
DR. LUKSENBURG: Dr. Cheson,
members of
13 the
committee, ladies and gentlemen, I'm Harvey
14
Luksenburg. I'm a clinical
reviewer at the Food
15 and
Drug Administration, and I would just like to
16
start off by noting that I am but a member of a
17
team of very talented individuals who put in a
18
tremendous amount of work in putting together the
19
data which we'll be presenting today.
20
Now, two large randomized studies in
21
cancer patients on chemotherapy plus or minus EPO
22
have shown shorter overall survival, shorter
85
1
progression-free survival, and an increased
2
incidence of thrombotic and cardiovascular events
3 in
the groups assigned to receive erythropoietins.
4
The erythropoietin products used in these
5 two
studies are not licensed in the U.S.
They are
6
NeoRecormon, epoetin beta, manufactured by
7
Hoffman-LaRoche, and EPREX, epoetin alfa, would is
8
manufactured by Ortho Biologics.
Both of these
9
studies used a treatment strategy to achieve a
10
hemoglobin greater than 12 grams per deciliter,
11
which is higher than that recommended in the
12
labeling for U.S.-licensed products.
13
The clinical trials for
U.S.-licensed EPO
14
products were not designed to assess the impact on
15
response rate, with one exception--the N93 study,
16
which I'll describe momentarily; they were not
17
designed to look at in a systematic way time to
18
progression or progression-free survival; and they
19
were not designed to look at overall survival.
20
Now, the goals of my talk are four-fold.
21
First of all, I'll try to give some justification
22 of
why the FDA feels that the safety issues
86
1
observed with EPREX and NeoRecormon, the
2
non-U.S.-licensed EPOs, may also apply to
3
U.S.-licensed products. In
addition, I will review
4
results of trials with EPREX and NeoRecormon, the
5
non-U.S.-licensed products, regarding the safety
6
concerns. Thirdly, I will review
data available
7
regarding safety from trials of EPOGEN/Procrit and
8
Aranesp, the U.S.-licensed trials, and finally will
9 try
to come agreement on the design of future
10
studies regarding these safety issues.
11
Now, the three safety issues which I'm
12
going to be discussing are, first of all, an
13
increased risk of thrombotic and cardiovascular
14
adverse events, an increased risk of tumor
15
progression in patients receiving EPO products, and
16
poorer survival in groups of patients receiving EPO
17
products.
18
Just the cast of characters.
Recombinant
19 EPO
products which are currently U.S.-licensed are
20
epoetin alfa manufactured by Amgen and marketed
21
under the name of EPOGEN; the same drug
22
manufactured by Amgen and marketed as Procrit by
87
1
Ortho Biotech; and darbepoetin alfa, or Aranesp,
2
manufactured and marketed by Amgen.
3
The EPO products which are not licensed in
4 the
U.S. are epoetin alfa, or EPREX, manufactured
5 by
Ortho Biologics; Epoetin beta, NeoRecormon,
6
manufactured by Hoffman-LaRoche.
7
Now, the FDA considers all these products
8
members of the same product class, and, thus, these
9
evolving safety issues are assumed to apply to all
10
products unless adequate and well-controlled trials
11
demonstrate otherwise.
12
The differences between these products are
13 as
follows: epoetin alfa and beta have the
same
14
amino acid sequence, but they differ in
15
glycosylation. Aranesp differs in
the amino acid
16
sequence (5) and in the degree of glycosylation.
17
The similarities are meaningful.
All
18
these exert their principal clinical effect by
19 binding to the erythropoietin receptor. All these
20
products have similar pharmacodynamic effects when
21
they're used at recommended dosages.
And there's a
22
similar toxicity profile across all of these
88
1
products with the exception of pure red cell
2
aplasia, which has been seen thus far only in
3
EPREX.
4
Now, target hemoglobin, the labels for
5
EPOGEN/Procrit and Aranesp have dosage guidelines
6
based on safety data from registration studies
7
performed in patients with chronic renal failure.
8
Just to quote what is written on the current
9
labels, for EPOGEN/Procrit, "The suggested target
10
hematocrit range is between 30 and 36 percent."
11 For
Aranesp, "The dose should be adjusted for each
12
patient to achieve and maintain a target hemoglobin
13 not
to exceed 12 g/dL."
14
In addition, for rapid increase in
15
hemoglobin greater than 1 gm per deciliter, or four
16
points in hematocrit, in any two-week period, the
17
dose should be reduced. And the
product should be
18
held if the hemoglobin is greater than 13 until the
19
hemoglobin falls less than or equal to 12 grams per
20
deciliter and re-start the dose at 25 percent below
21 the
previous dose.
22
Now, the first safety issue which I'd like
89
1 to
discuss is that of an increased incidence of
2
thrombotic and cardiovascular adverse events. This
3 is
a road map, and I'll show this slide several
4
more times, and for each safety issue--thrombotic
5
events, tumor progression, overall survival--I'm
6
going to discuss only one study done in renal
7
patients, the Normal Hematocrit Study.
These in
8
yellow are the studies done in non-U.S.-licensed
9
EPO, and the studies in pink are the studies done
10 in
U.S.-licensed EPO products. An
"x" means that
11
there's data available for evaluation for each of
12
these safety concerns.
13
Now, the licensing studies for
14
EPOGEN/Procrit and Aranesp demonstrated that
15
there's a baseline risk of thrombotic and
16
cardiovascular adverse events at their labeled
17
target hemoglobin, that is, between 10 and 12 grams
18 per
deciliter.
19
A study which dramatically showed the
20
potential adverse effects of increasing the
21
hemoglobin was the so-called Normal Hematocrit
22
Study, first author Besarab, published in the New
90
1
England Journal in 1998. The idea
behind this
2
study was that patients with chronic renal failure
3 on
dialysis who had clinical evidence of cardiac
4
disease could do better clinically if they had
5
their hemoglobin raised from the nominal low 30
6
range to a higher hematocrit, around 40.
And so
7
1,200 patients with chronic renal failure on
8
dialysis with clinical evidence of congestive heart
9
failure or ischemic heart disease, they were all on
10
EPOGEN at baseline and maintaining a hematocrit of
11
between 27 and 33 percent.
12 Now, both arms received EPOGEN, but
they
13
were randomized to different treatment strategies.
14 One
was randomized to achieve a higher hematocrit,
15
around 42, plus or minus 3. This
was called the
16
so-called normal hematocrit group.
The other arm
17
maintained the lower hematocrit group, as was
18
customary in practice, around 30 percent. This was
19
called the low hematocrit group.
20
This study had a composite primary
21
endpoint of either death or non-fatal myocardial
22
infarction, and here are the results.
In the
91
1
normal hematocrit group, there's an increased
2
incidence of death, 30 percent, versus 34 percent
3 in
the low hematocrit group. There's an
increased
4
risk of non-fatal myocardial infarction, 3.1
5
percent in the normal hematocrit group, versus 2.3
6
percent in the low hematocrit group.
And there was
7 an
increased risk of vascular access thrombosis, 39
8
percent in the normal hematocrit group versus 29
9
percent in the low hematocrit group.
10
Here's a graph showing the increased
11
probability of death in the normal hematocrit
12
group, death or myocardial infarction in the normal
13
hematocrit group, and in the low hematocrit group.
14
This goes out to about 30 months.
15
Now, when I talk about target hemoglobin,
16 a
target hemoglobin is only a target, and many
17
patients don't achieve that target.
However--and
18
this has been seen in both the renal studies and in
19 the
oncology studies--it's the dosing strategy, it
20 is
the idea of pushing the dose of the
21
erythropoietin to a higher level in order to try to
22
attain the target hemoglobin.
However, we've seen
92
1 in
all these studies that the adverse event signals
2
seem to occur in the group assigned to the dosage
3
strategy aimed at the target hemoglobin, despite
4
whether they attained that hemoglobin or not.
5
Now, the next studies I want to discuss
6 are
the BEST and the Henke studies. These
are the
7
studies done in oncology patients using
8
non-U.S.-licensed erythropoietins.
And, again, I'm
9
just talking about thrombotic events.
10
The Breast Cancer Erythropoietin Trial, or
11 the
BEST Trial, used EPREX. This was a
randomized,
12 double-blind,
placebo-controlled trial in 939
13
patients with metastatic breast cancer who were
14
receiving first-line therapy.
They received EPREX
15 or
placebo for 12 months, and the therapy was not
16
started until the hemoglobin was less than 13.
17
The primary objective of this study was to
18
demonstrate superior survival at 12 months. The
19
target hemoglobin, again, was higher than what is
20 on
the label, between 12 and 14, and this study was
21 stopped
by an Independent Data Monitoring Committee
22
based on the first four months of safety data.
93
1
At four months, there was an increase
2
incidence of fatal thrombotic and cardiovascular
3
events. In the EPREX arm, it was
2.3 percent; in
4 the
placebo arm, it was 0.4 percent.
5
The next trial that got our attention was
6
published in The Lancet last October by Henke and
7 his
colleagues, and it used NeoRecormon, or epoetin
8
beta. This was a randomized,
double-blind,
9
placebo-controlled trial in 351 patients with head
10 and
neck cancer who were receiving concurrent
11
radiation therapy. All these
patients were anemic,
12
less than 12 grams per deciliter in women, less
13
than 13 grams per deciliter in men.
14
The primary objective in this trial was to
15
demonstrate superior locoregional progression-free
16
survival. The target hemoglobin
was less than or
17
equal to 14 in women and less than or equal to 15
18 in
men.
19
Now, the incidence of cardiovascular and
20
thrombotic events was higher in the epoetin beta
21
arm, 11 percent, versus placebo--this included
22
hypertension, hemorrhage, venous thrombosis,
94
1
pulmonary embolism, and stroke.
In addition, the
2
incidence of patients who died of cardiac disorders
3 not
otherwise specified was 5 percent in the
4
epoetin beta group versus 3 percent in the placebo
5
group.
6
Next, still in the thrombotic events
7
column, I'm going to discuss the studies we have
8
available to us on the U.S.-licensed epoetin
9
products.
10
The registration studies for Procrit
11
consisted of pooled analyses of six multicenter,
12
randomized, double-blind, placebo-controlled
13
studies constituting a total of 131 patients. They
14 had
various primary cancers. Three of these
15
studies consisted of patients receiving
16
platinum-containing chemotherapy and three of them
17
consisted of patients receiving
18
non-platinum-containing chemotherapy.
All these
19
patients were anemic, and the primary endpoint was
20
proportion of patients transfused.
There were no
21
progression-free survival or survival endpoints
22
incorporated in these studies.
95
1
The incidence of thrombotic and
2
cardiovascular events in the pooled data was 12
3
percent in the placebo group and 3 percent in the
4
Procrit group.
5
A post-marketing commitment study done
6
after the approval of EPOGEN/Procrit for the
7
oncology indication asked the question whether
8
giving Procrit along with chemotherapy for
9
small-cell carcinoma of the lung would have a
10
potential adverse effect on the tumor's response to
11
chemotherapy. This was a
randomized, double-blind,
12
placebo-controlled, non-inferiority study which was
13
intended to enroll 400 patients with small-cell
14
carcinoma of the lung who were receiving first-line
15
therapy and their baseline hemoglobin was less than
16
14. So these patients did not
necessarily have to
17 be
anemic.
18
The primary endpoint, as I mentioned, was
19 the
objective response rate, CR plus PR, after
20
three cycles of chemotherapy to rule out a
21
decrement of 15 percent in the overall response
22
rate with Procrit. There was no
target hemoglobin;
96
1
however, the Procrit dose was reduced if the
2
hemoglobin exceeded 16 grams per deciliter. The
3
study, however, was terminated because of poor
4
accrual at 224 patients.
5
Now, the incidence of thrombotic and
6
vascular events in this study--we did review the
7
data after 224 patients--in the Procrit group was
8 22
percent and in the placebo group was 23 percent.
9
However, the definition of thrombotic and vascular
10
events included chest pain, not otherwise
11
specified, as well as all the other well-known
12
clinical entities. So we
subtracted chest pain and
13
came up with these figures: for
the Procrit group,
14 the
incidence of thrombotic/vascular events went to
15 14
percent, and in the placebo group, it was 9.5
16
percent.
17
The Aranesp Oncology Registration Study
18 was
a randomized, double-blind, placebo-controlled
19
study in 320 patients with both small-cell and
20
non-small-cell lung cancer, all of who were
21 receiving
platinum-containing chemotherapy. All
22
these patients were anemic.
97
1
The primary endpoint, again, was a
2
transfusion endpoint, the proportion of patients
3
transfused between week 5 and week 12 or the end of
4 the
treatment period. The dosage guidelines
were
5
that Aranesp was to be held for hemoglobin of
6
greater than or equal to 14 in women and for
7
greater than or equal to 15 in men.
8
The incidence of thrombotic events in this
9
study was 5 percent in the Aranesp group and 3
10
percent in the placebo group.
11
So, to summarize the studies for the
12
thrombotic/cardiovascular events so far, in the
13
studies in which a signal was detected, the Normal
14
Hematocrit Study done in patients with chronic
15
renal failure, the incidence of non-fatal
16
myocardial infarction, 3.1 percent in the normal
17
hematocrit group versus 2.3 percent in the low
18
hematocrit group. An increased
incidence of
19
vascular access thrombosis, 39 percent in the
20
normal hematocrit group versus 29 percent in the
21 low
hematocrit group. In the BEST Study,
done in
22 939
patients with metastatic breast cancer, there
98
1 was
an increased risk of fatal thrombotic events in
2 the
arm randomized to receive EPREX, 2.3 percent,
3
versus 0.4 percent in the placebo arm.
4
In the Henke Study in head and neck cancer
5 and
the patients were randomized to receiving
6
epoetin beta, or NeoRecormon, or placebo, there was
7
also an increased risk of cardiovascular and
8
thrombotic events, 11 percent in the epoetin beta
9
group versus 5 percent in the placebo group.
10
In the thrombotic and vascular events
11
studies that didn't have a signal, the Procrit
12
pooled studies, 3 percent in the Procrit group
13
versus 12 percent in the placebo group.
The N93
14
study in small-cell carcinoma of the lung, 22
15
percent Procrit versus 23 percent placebo. We put
16 an
asterisk next to this because after we
17
subtracted the non-specific chest pain, we did find
18
that there was an increased risk of
19
thrombotic/vascular events in the Procrit group.
20
And, finally, the Aranesp Oncology Registration
21
Study, 5 percent incidence in the Aranesp group
22
versus 3 percent in the placebo group.
99
1
Now, in September 2003, three
2
placebo-controlled clinical trials in oncology
3
patients in which one arm received EPO to target a
4
higher hemoglobin were terminated because of
5
unexpected rates of thrombotic events in the EPO
6
arm.
7
Briefly, to summarize these studies, in
8
one, the primary cancer was small-cell carcinoma of
9 the
lung; the target hemoglobin was between 14 and
10 16;
the incidence of thrombovascular events, TVE,
11 was
34 percent in the EPREX group versus 6 percent
12 in
the placebo group. The second study,
patients
13 who
had cervical cancer, the target hemoglobin was
14
between 13 and 14; the incidence of TVE, 16 percent
15 in
the Procrit group, versus 5 percent in the
16
placebo group. And the third
study, gastric or
17
rectal carcinoma, target hemoglobin 14 or 15; the
18
incidence of TVE, 24 percent in the Procrit group
19
versus 6 percent in the placebo group.
20
Now, the next safety issue I'd like to
21
discuss is that of tumor progression.
There are a
22
number of preclinical studies which have been
100
1
reviewed, but our selective take under the
2
literature is that there are EPO receptors which
3 are
present on some tumor cell lines and on tumor
4
vasculature, meaning endothelial cells.
5
EPO has been reported in some studies to
6
inhibit apoptosis, stimulate angiogenesis,
7
stimulate endothelial cell growth, migration, and
8
proliferation, and reduce survival in some tumor
9
xenograft models.
10
Now, studies supporting the approval of
11
Procrit and Aranesp for the treatment of anemia in
12
cancer patients on chemotherapy were not designed
13 to
assess the impact on tumor response, tumor
14
progression, or survival. So
there's a big lacunae
15 in
the information that we have for the
16
U.S.-registered EPO products.
And, again, I'm
17
going to go through the two studies that utilized
18
non-U.S.-licensed EPO products and then two studies
19
which we have that have data that's useful for
20
looking at tumor progression in the U.S.-licensed
21 EPO
products.
22
Again, just to remind you that the BEST
101
1
Study using EPREX, randomized, double-blind,
2
placebo-controlled, 939 patients with metastatic
3
breast cancer, first-line therapy, randomized to
4
receive EPREX or placebo for 12 months, therapy
5
started at less than 13.
6 The primary objective of this
study was to
7
demonstrate superior survival at 12 months. The
8
target hemoglobin was between 12 and 14, and this
9
study, again, was stopped by the Data Monitoring
10
Committee based on the first four months of safety
11
data.
12
At four months, there was a twofold
13
increase in the incidence of disease progression.
14 It
was 6 percent in the EPREX group and 3 percent
15 in
the placebo group.
16
At four months, there was 2.5-fold
17
increase in early mortality. It
was 8.7 percent in
18 the
EPREX group versus 3.4 percent in the placebo
19
group.
20
In the Henke trial, again, randomized,
21
double-blind study in 351 patients with head and
22
neck cancer receiving concurrent chemotherapy,
102
1
these patients were entered if women had a
2
hemoglobin of less than 12 and men less than 13.
3 The primary objective was to demonstrate
superior
4
locoregional progression-free survival.
The target
5
hemoglobin was less than or equal to 14 in women or
6
less than or equal to 15 in men.
7
For locoregional progression-free survival
8 as
the primary endpoint, the relative risk was 1.62
9
favoring placebo, and the lower bound or the
10
95-percent confidence interval was greater than 1,
11
with a highly significant p value.
12
For locoregional progression, again, the
13
relative risk was 1.69 favoring placebo and the
14
lower bound of the 95-percent confidence interval
15 was
greater than 1, with a significant p value.
16
Study N93, the post-marketing study which
17
looked at small-cell carcinoma, this was a
18
randomized, double-blind, non-inferiority study
19
which was intended to enroll 400 patients who were
20
receiving first-line therapy.
21
The primary endpoint, again, was objective
22
response rate after three cycles of chemotherapy to
103
1
rule out a 15-percent decrement in the overall
2
response rate in the Procrit arm.
No target
3
hemoglobin was determined. The
Procrit dose was
4
reduced for hemoglobins greater than or equal to
5 16,
and the study was terminated at 225 patients
6 out
of a projected 400 for poor enrollment.
7
This study was not designed to assess the
8
impact on time to progression, and survival was a
9
secondary endpoint, and there was no formal
10
hypothesis testing.
11
The results showed that for the placebo
12
group the overall response rate was 67 percent; for
13 the
Procrit group it was 72 percent. The
14
95-percent confidence interval around the observed
15
difference had a lower bound of minus 6 percent.
16 So
even though this study met its intended
17
objective despite the early termination, it was
18
able to exclude a difference of greater than 15
19
percent.
20
The Aranesp Oncology Registration Study, a
21
randomized, double-blind, 320 patients with
22
non-small-cell and small-cell lung cancer all
104
1
receiving platinum chemotherapy and all of whom
2
were anemic.
3
The primary endpoint was a transfusion
4
endpoint. The Aranesp was held
for hemoglobins
5
greater than 14 in women and 15 in men.
6
The median progression-free survival was
7
five months in the Aranesp group and four months in
8 the
placebo group. This study, again, was
not
9
designed to assess the impact on progression-free
10
survival.
11
And here are the curves. This is
the
12
placebo group here. Here is the
Aranesp group.
13
Here is a year, two years.
14
So, just to summarize, the data we have on
15
tumor stimulation, first the studies in which a
16
signal was detected. The BEST
Study, EPREX,
17
metastatic breast cancer, at four months an
18
increased risk of deaths due to disease progression
19
being 6 percent in the EPREX group versus 3 percent
20 in
the placebo group. In the Henke Study,
head and
21
neck carcinoma using NeoRecormon, EPO B, the
22
relative risk for locoregoinal progression-free
105
1
survival favored placebo, 1.62.
2
The tumor stimulation studies without a
3
signal, the Procrit group, the post-marketing
4
commitment in small-cell carcinoma of the lung, the
5
overall response rate was 72 percent in the Procrit
6
group versus 67 percent in the placebo group. The
7
Aranesp Oncology Registration trial, the median
8
progression-free survival, four months for Aranesp,
9
five months for placebo.
10
And, finally, I'd like to discuss the data
11 we have
concerning poorer survival in patients
12
randomized to receiving erythropoietins.
13
Again, I'll be discussed the data we have
14 on
the BEST trial and the Henke trial as well as
15 the
U.S.-licensed erythropoietins.
16 Just to remind you once again, the
breast
17
cancer study, 939 patients with metastatic breast
18
cancer, randomized to receive EPO or--EPREX or
19
placebo for 12 months, and the primary objective of
20
this trial was to demonstrate superior survival at
21 12
months. The target hemoglobin was
between 12
22 and
14, and this study was stopped by the
106
1
Independent Data Monitoring Committee based on four
2
months safety data.
3
The estimated 12-month survival was 70
4
percent in the EPO group and 76 percent in the
5
placebo group. The relative risk
of death was 1.4
6
favoring the placebo group, and the lower bound of
7 the
95-percent confidence interval was greater than
8 1,
with a p value of 0.12.
9
Here are the curves for the first 12
10
months, which was the primary endpoint.
This is
11 the
placebo group on top, and here is the EPREX
12
group.
13
In the Henke Study, again, 351 patients
14
with head and neck cancer getting radiation
15
therapy. The erythropoietin
product used was
16
NeoRecormon.
17
The relative risk of death was 1.4
18 favoring
placebo; the lower bound of the 95-percent
19
confidence interval was greater than 1.
The median
20
overall survival was not different, but there's a
21
trend toward poorer survival in the NeoRecormon
22
group--was 605 days in the NeoRecormon group versus
107
1 928
days in the placebo group.
2
Study N93, the post-marketing commitment
3
done in patients with small-cell carcinoma of the
4 lung,
again, this study was not designed to assess
5 an
impact on survival. The median survival
was
6
10.5 months in the Procrit group and 10.4 months in
7 the
placebo group. The overall mortality
rate was
8 92
percent in the Procrit group versus 88 percent
9 in
the placebo group.
10
And here are the curves. The
dotted line
11 is
the placebo group. The sold line is the
Procrit
12
group.
13
The Aranesp Oncology Registration trial,
14 320
patients with lung cancer receiving
15
platinum-containing chemotherapy.
This study was
16 not
designed to assess the impact on survival.
17
The median overall survival was ten months
18 in
the Aranesp group and eight months in the
19
placebo group. The overall
mortality rate, 14
20
percent in the Aranesp group, and 12 percent in the
21
placebo group.
22
And this is the placebo arm here, and here
108
1 is
the Aranesp arm. This is one year, two
years.
2
And so, just to summarize the studies we
3 had
in which there was a survival signal, the BEST
4
Study, metastatic breast cancer, the 12-month
5
survival rate, the primary endpoint, poorer
6
survival in the EPREX group, 70 percent, versus 76
7
percent in the placebo group, p value of 0.12. In
8 the
Henke Study using NeoRecormon, the median
9
overall survival not significant but a trend, 605
10
days for NeoRecormon versus 928 days with placebo.
11
The studies that we have without a
12
survival signal, the N93 Study, post-marketing
13
study in small-cell carcinoma of the lung, 10.5
14
months in the Procrit group versus 10.4 months in
15 the
placebo group. The Aranesp Oncology
16
Registration Study, ten months in the Aranesp group
17
versus eight months in the placebo group.
18
So, to summarize, two large, multicenter
19
studies--the BEST Study and the Henke Study--which
20
were designed to show superior survival or
21
progression-free survival, instead demonstrated an
22
increased risk of thrombotic and cardiovascular
109
1
events, a shorter progression-free survival, and a
2
shorter overall survival. Both of
these studies
3
used a treatment strategy to achieve hemoglobin
4
levels greater than or equal to 12.
5
The multicenter, placebo-controlled trials
6
using Procrit and Aranesp, the U.S.-licensed
7
erythropoietins, were smaller in size; they were
8 not
designed to assess the impact on
9
progression-free survival or overall survival.
10
Their treatment strategy varied:
Procrit was held
11 in
the N93 Study for hemoglobin greater than
12
14--the label recommends 12--and in the Aranesp
13
study it was held for greater than 14 in women or
14
greater than 15 in men.
15
So, to conclude, we have these evolving
16
safety concerns. They cannot be
dismissed. The
17
current dosing recommendations we feel are adequate
18 to
minimize the risk of thrombotic events.
19
However, there is insufficient information
20 concerning
overall survival and progression-free
21
survival for U.S.-licensed products at approved
22
doses to assess these risks.
Amgen, Ortho Biotech,
110
1 and
the FDA have agreed on the need for further
2
studies to investigate these safety issues.
3
Now, the FDA recommends certain elements
4
that should be components of all current and future
5
studies which will be done to investigate these
6 safety issues. First of all, there should be a
7
homogeneous primary tumor type.
There should be
8
homogeneous chemotherapy or radiotherapy regimes.
9 The
studies should be designed to detect clinically
10
meaningful decrements in response rate,
11
progression-free survival, and survival.
There
12
should be prespecified definitions of
13
cardiovascular and thrombotic events.
And there
14
should be Data Safety Monitoring Committee
15
oversight.
16
We also recommend the
determination of
17
expression and ligand affinity of EPO receptor on
18
specific primary tumor types, preferably through
19 the
analysis of clinical tissue specimens or
20
through pre-existing tissue repositories
21
representing common tumor types.
22
And I think that is the end of my
111
1
presentation.
2
DR. CHESON: Thank you, Dr.
Luksenburg.
3
It's now time for questions from the
4
committee to either the sponsor or Dr. Luksenburg.
5 I'd
like to start, while all the people are coming
6 up,
with questions for Dr. Luksenburg. On
your
7
various slides, Harvey, when you're talking about
8
studies with signals, you mean with negative
9
signals, since there are a number of studies with
10
positive signals, including one of the ones on your
11
slide, 98-0297, with the ten- versus eight-month
12
survival in favor of the erythropoietin compound,
13
right? So when you say with
signal, you're
14
referring to negative signal in your slides.
15
DR. LUKSENBURG: Yes.
16
DR. CHESON: Okay.
17
DR. KEEGAN: I would point out
that the
18 one
that you're referring to as having the positive
19
signal is actually not significantly different.
20
DR. CHESON: I know, but neither
are some
21 of
the others.
22
Any other questions from the committee?
112
1 Any
comments from the committee? Dr.
Martino?
2
DR. MARTINO: I'm reminded of a
quote from
3
Enrico Fermi, which goes as follows:
"Before I
4 came
here, I was confused on this topic. Now
I'm
5
still confused, but at a somewhat higher level."
6
[Laughter.]
7
DR. MARTINO: And I'm not sure who
I want
8 to
sort of address this to, but whoever of you
9
thinks you have an answer, I'd appreciate it.
10
It occurs to me that looking at the tumor
11
tissue itself to see if it has receptors certainly
12 is
reasonable if it's doable. Simultaneous
to
13
that, it is likely that the mechanism, if there is
14 any
by which tumors grow, may not be by direct
15
involvement of the tumor cell itself, but may be
16
through some other mechanism. One
of those, you
17
know, is what it might do to the vascular system
18 and
neovascularization.
19
Is there some way to look at that
20
parameter? Because some of us
think that that may
21 be
the more likely mechanism by which tumor cell
22
growth may occur, if, in fact, it does.
113
1
DR. CHESON: Dr. DeLap?
2
DR. DeLAP: Yes, I'd like to ask
Dr.
3
Francis Farrell to address that question. Dr.
4
Farrell is head of our preclinical program for this
5 area.
6
DR. FARRELL: Thanks for the
excellent
7
question. Francis Farrell,
Johnson & Johnson.
8
We feel that your idea does have credence.
9
Although we don't feel that the receptor on tumor
10
cells is functional, there is enough preclinical
11
data to show that EPO does have an effect on
12
endothelial cell function, including some papers
13
showing that EPO binds to endothelial cells. There
14
have been some studies showing some chemotaxis with
15 EPO
on endothelial cells. There's also been
some
16
data that aortic ring formation can be formed.
17
The only caveat with these experiments,
18
though, are that high doses of EPO are actually
19
used to see this effect. And in
one publication,
20 the
dose used was actually 50 units per ml, which
21
would be very high compared to what the clinical
22
maximal serum dose a patient would get with 40 IUs
114
1 per
kg dose, which is approximately two units per
2 ml.
3
So to answer your question, though, I
4
think better preclinical modeling and xenograft
5
models where you could actually look at vascular
6
density, micro-vessel formation, I think are
7
warranted, and that would be the direction that we
8
would go in.
9
DR. DeLAP: If I could ask your
10
indulgence, we also have Dr. Kimberly Blackwell
11
here who could also contribute to this point, I
12
think, as a consultant, if we have a minute.
13
DR. CHESON: Please. That would be fine.
14
DR. BLACKWELL: Hi. I'm Kim Blackwell
15
from Duke University.
16
I, like the questioner, had some interest
17 in
was this tumor effect, was it endothelial cell
18
effect, and we've embarked on a number of
19
preclinical modeling, now with well over 500
20
animals that we've looked at, both in R3230, which
21 is
an ER-positive mammary carcinoma line.
So it's
22 as
close as you can get to a rodent model to human
115
1
model. We've also looked at CT26,
which is a
2
colorectal model.
3
So, very briefly, our
experiments have
4
looked at tumor proliferation using Key 67, tumor
5
growth using biodimensional tumor volume. We've
6
also looked at micro-vessel density, and I think
7 the
best experiment is we've actually looked at in
8
vivo angiogenesis using a dorsal window fold where
9 you
can actually measure vascular development in
10 the
mammary carcinoma model. And I will say
that
11
we've looked at erythropoietin in close to 16
12
mammary carcinomas and have failed to see any
13
effect on tumor growth, tumor proliferation, or
14
tumor angiogenesis. Obviously the
in vivo
15
angiogenesis models involve a small number, about
16 25
animals, because those are difficult experiments
17 to
do.
18
We've also looked at darbepoetin using
19
similar models in both R3230 and CT26 that was
20
alluded to the Aranesp presentation, and using
21
biodimensional models in over 200 animals with
22
R3230 tumors have failed to see effect on tumor
116
1
growth, tumor proliferation, and angiogenesis
2
measured by micro-vessel density.
3
So I agree with Dr. Farrell that this
4 really needs to be studied further in in vivo
tumor
5
models because the interaction between tumor
6
endothelial cells, that's really the only way to
7
study it as opposed to studying endothelial cells
8 or
tumor cells separately in cell culture models.
9
DR. VIVEASH: I'd like to ask Dr.
Losordo
10 to
make some comments relating to this issue.
11
DR. CHESON: Please.
12
DR. LOSORDO: I'm Dr. Losordo from
Tufts
13
University and St. Elizabeth's Medical Center in
14
Boston. My expertise is actually
in cardiovascular
15
where we've been studying actually the stimulation
16 of
angiogenesis for various ischemic disorders.
17 And
that experience I think has bearing here
18 because the patient population that we study,
which
19 is
generally aged and, therefore, it is somewhat
20
higher risk for cancer than the general population,
21
forces us to analyze the potential risk of
22
stimulating angiogenesis in those patients in
117
1
various in vivo models. And so as
a result of our
2
work primarily using VEG-F to stimulate
3
neovascularization of ischemic tissue, we've also
4 conducted
studies analyzing the impact of
5
stimulating angiogenesis in that context on tumor
6
vascularization and tumor progression by implanting
7
tumors into animals and then stimulating
8
angiogenesis by exogenous administration of
9
angiogenic cytokines and have found, in fact,
10
interestingly, that the angiogenesis that's
11
stimulated is very context-dependent, meaning that
12 in
the region where angiogenesis seems to be
13
deficient, for example, in the myocardium or the
14
lower extremity where we've induced ischemia, the
15
exogenous cytokine can stimulate and improve
16
perfusion of that tissue. While
the tumor itself
17
regresses under the influence of chemotherapy, the
18
vascularity of the tumor does not change at all.
19
And so what we've learned in a number of
20
studies, and that would now include also studies in
21
which we're using progenitor cells from the bone
22
marrow or peripheral circulation, to also augment
118
1
neovascularization of ischemic tissue, and in those
2
instances either stimulating the release of those
3
progenitor cells from the marrow or directly
4 implanting them into ischemic tissue also does
not
5
influence tumor progression.
6
So I would say that at the same time the
7
study of these things is of great interest and
8
something that we'll likely do and continue to do
9 in
the context of generating safety data for
10
ongoing clinical studies.
However, it also seems
11 to
me that all those preclinical studies, while
12
generating interesting science, will not trump the
13
sort of clinical trial data that's being generated
14 and
continuing to be generated, which I think will
15
influence patients and clinicians to a far greater
16
degree.
17
DR. CHESON: Thank you.
18
Are there any other investigators who
19
would like to comment on this particular topic?
20
[No response.]
21
DR. CHESON: Okay. We can move on then.
22
Other questions from the panel?
Dr. George,
119
1
please.
2
DR. GEORGE: I have a question for
Dr.
3
Luksenburg. That was a very
thorough presentation,
4 but
I was a little puzzled by the way it was
5
presented with respect to studies that showed a
6
signal, those that didn't show a signal, and I was
7
left trying to do my own mental meta-analysis of
8
things to try to get some bottom line there.
9
Did you do such things? Or can
you help
10 us
out in that way?
11
DR. LUKSENBURG: No, we
didn't. We
12
obviously reviewed data which had come in over a
13
number of years, and much of this data was from
14
registration studies which were a few years old,
15 and
we looked, as did the sponsors, for evidence
16
of--we looked at the data that was there for
17
overall survival and progression-free survival.
18 But
since the studies were not designed to look at
19
that, we, you know, just--we took the data as it
20
was. We did not do any meta-analyses.
21
In general, our stance is that the studies
22
that are valuable are studies--except for
120
1
thrombotic/cardiovascular disease, the studies that
2
will provide the best quality data for overall
3
survival, progression-free survival, time to tumor
4
progression, are those with homogeneous tumor
5
populations. And it's really
difficult to do
6
meta-analyses with variegated tumor populations.
7
DR. CHESON: Dr. Keegan, did you
want to
8
make a comment?
9
DR. KEEGAN: Yes. Actually, that was one
10 of
our concerns with several of the meta-analyses
11
presented, that it's trying to put the data in
12
there in a way that--and take studies that weren't
13
intended to look at these events and provide
14
information. And I think the
quality of many of
15 the
studies included in the meta-analysis are not
16 the
same in terms of what information they can give
17 you
on progression-free survival or on overall
18
survival simply because of the heterogeneity and
19 the
lack of control. So that, you know, I
think if
20 we
were to choose to select the studies, we would
21 try
and find studies that were actually designed to
22
look at these endpoints and have the qualities that
121
1 we
are recommending further.
2
DR. GEORGE: Just a quick
follow-up. I
3
certainly agree with respect to some of those
4
endpoints, but survival should be a clear one.
5
DR. KEEGAN: I think when you look
at some
6 of
those studies--and many of them are fairly small
7
studies, and they enrolled any patient with any
8
tumor at any stage in their treatment.
It might
9
tell us something about transfusion rates. That's
10
what they were intended to do.
But they weren't
11
really intended to give us a good comparison of
12
impact on tumors. These studies
were really done
13 in
a manner not well designed to assess impact on
14
tumor, just given all the incredible variables so
15
much more important in terms of impact on survival
16 and
time to progression.
17
Presumably, if there had been thousands of
18
patients, all of those variables would probably
19
have been evened out. But most of
the studies, as
20 you
look at them, are not particularly large, with
21 the
exception of the ones that we tried to
22
highlight.
122
1
DR. CHESON: Are you satisfied
with that
2
answer, Dr. George?
3
DR. GEORGE: Yes.
4
DR. CHESON: Okay. Ms. Mayer?
5
MS. MAYER: As I understand it,
FDA is
6
coming to ODAC not to ask us to assess if there is
7 any
level of risk associated with these products,
8 but
given that there may be a level of risk, to
9
look at what kinds of clinical trials need to be
10
done. And I'm wondering since the
data doesn't
11
seem to be conclusive, since there are different
12
perspectives, if it's useful for us to continue to
13 try
to assess what we know already from the trials.
14
It's just a question, I guess a clarification of
15
what our task is.
16
DR. KEEGAN: I think you're right
in
17
saying that if we thought we knew the answer, we
18
wouldn't be asking you to reinterpret the data for
19
us. I think we're saying that we
don't think it's
20
been definitively assessed and could we seek some
21
guidance on how to really address this question.
22
DR. CHESON: And the way I see it
is we're
123
1
being asked to do one of several things:
one,
2
decide if the data are of sufficient concern; two,
3 if
they are of sufficient concern, are additional
4
studies warranted; and, three, if additional
5
studies are warranted, are those the studies that
6 are
already ongoing, as clearly elucidated by Dr.
7
Parkinson and his colleagues.
8
Dr. Bauer, please?
9
DR. BAUER: Yes, maybe I could just follow
10 up
on that point, because some of the studies we've
11
heard presented clearly are driven by safety
12
concerns in terms of showing safety, but, you know,
13 as
I understand the studies that are being
14
proposed, there's really a desire to show improved
15
survival. And I guess we haven't
heard a great
16
deal about the rationale really in terms of showing
17
survival. I think we know about
effects on
18
radiotherapy and tumor oxygenation.
We also know
19
some of the high hematocrits targeted there clearly
20 are
detrimental and a desire in all the studies
21
going forward to keep the hematocrit below certain
22
specified levels. I guess I would
like to hear
124
1
more about really the rationale for really at this
2
point believing that there really will be improved
3
progression-free survival with the use of some of
4 these
erythropoietic stimulating agents, or
5
survival overall, especially given the clear
6
detrimental effect, albeit it small, in terms of
7
thrombosis.
8
DR. CHESON: I think that most of
these
9 are
probably non-inferiority trials, if I'm not
10
mistaken. They just don't want to
show that there
11 is
a negative effect.
12
Dr. Parkinson, since you were reviewing
13 all
those articles, would you like to comment on
14
that, please?
15 DR. PARKINSON: Dr. Bauer, you're correct
16 in
that we did not spend a lot of time talking
17
about the rationales. The time
was short.
18
Sponsors were many.
19
There is a wealth of preclinical evidence
20
which I think there are a number of people who
21
could discuss in more detail.
There is a
22
significant amount of clinical evidence.
I
125
1
referred to the Cochran meta-analysis, independent
2
analysis conducted, as you're aware, by the Cochran
3
group, which was considered to be suggestive
4
enough--not definitive, but suggestive enough to
5
warrant further trials. I mention
that because I
6
think it's important. It's
dissociated from any
7
product-related.
8
We've shown you and you've seen from other
9
sponsors quite interesting suggestions of patient
10
benefit in a number of defined settings, both of
11
radiotherapy and chemotherapy.
Additionally, the
12
trials that I described which were not
13
Amgen-sponsored were initiated by independent
14
investigators based on their own independent
15
assessment of preclinical and clinical data
16
designed to test particular hypotheses, which are
17
actually superiority hypotheses.
These were not
18
trials designed to look for negative survival
19
signals with erythropoietins.
These were trials
20
designed to look for benefit based on--we won't
21
give you our assessment of the literature--their
22
assessment of the literature and what they believed
126
1
were important therapeutic questions to ask.
2
You know, we can go into as much
3
detail--there are actually investigators here from
4
each of those particular clinical groups. There
5 are
preclinical investigators here from at least
6 two
companies. There's a wealth of evidence
to
7
support this kind of investigation.
What we see
8
here today are two signals from two trials which
9
you've heard described and analyzed in great
10
detail. You can make your own
judgment as to what
11 the
value of those signals is.
12
DR. CHESON: Dr. DeLap?
13
DR. DeLAP: Since we've also
14
done--obviously we've done a number of trials in
15
this area. We clearly have a
rationale for
16
proceeding in this area. I'd like
Dr. Adrian
17 Thomas to address our thoughts in this area.
18
DR. THOMAS: Good morning and
thank you.
19
Adrian Thomas, Vice President, Drug Safety, Johnson
20
& Johnson.
21
I think our view and position is entirely
22
consistent with Dr. Parkinson.
It's entirely
127
1
reasonable to look for survival benefits with these
2
products, and we indeed embarked on INT-76 as a
3
result of results from INT-10, in which we
4
demonstrated as a secondary endpoint of survival
5
advantage and, more particularly, when we looked at
6 the
subgroup of patients with breast cancer, they
7
seemed to benefit the most.
8
So I think the rationale for pursuing a
9
survival advantage is there. It's
clearly in the
10
context of what the risks might be in terms of,
11
from our perspective, thrombotic vascular events
12 and
the appropriate targeting of hemoglobin levels.
13 DR. CHESON: Dr. Weiss?
14
DR. WEISS: Just to, I guess,
reiterate
15
what has been said, there is a wealth of data,
16
there's a lot of information, lots of variability
17 in
terms of the quality of the different studies,
18 and
I know it's a difficult question to try to sort
19
through it all. I think we all
agree, though, that
20
there's some provocative and interesting
21
information that might suggest some benefits other
22
than just minimizing or avoiding transfusions with
128
1
erythropoietin products, and I think we'd all like
2 to
be able to document that and have that well
3
established. I think there's
maybe a belief system
4
that erythropoietins are benign, with the exception
5
perhaps of some slight increased risk in thrombotic
6
events.
7
So I think the question here is--and we've
8
certainly had lots of discussions with both Amgen
9 and
J&J. I think we all agree that there
is room
10 for
further studies and further exploration, and
11 the
best way to try to show a survival benefit or
12
disprove some type of disadvantage is to do it in
13 the
context of very good, well-designed clinical
14
trials. And I really think that's
really the focus
15 of
this particular meeting.
16
DR. CHESON: Dr. Parkinson,
pleaseS?
17
DR. PARKINSON: Just to say we
totally
18
agree and that, although I indicated that these
19
trials were designed to look for superiority in
20
terms of the therapeutic beneficial effects of
21
Aranesp in our case, I just had a little note from
22 my
statistical colleagues that, you know, just
129
1
because they're designed to show superiority
2
doesn't mean that they can't have a huge value in
3
looking for negative survival signals.
So to keep
4
myself statistically in good company, I wanted to
5
point that out.
6
DR. CHESON: Thank you.
7
Dr. Martino?
8
DR. MARTINO: I just need to be
sure I'm
9
clear before I say anything semi-intelligent here.
10 I
need to be sure that I'm understanding the
11
following: It occurs to me that
there really are
12 two
trials that have shown tumor-specific bad
13
qualities, and those trials share at least one
14
thing in common, which is that they've aimed for a
15
hemoglobin above and beyond what most of us
16
considered usual and appropriate and normal and the
17
aim, at least within this country.
18
And so as we think about what questions we
19
need to answer, it occurs to me that that's a key
20
point as to are we trying to show that something
21 bad
happens, are we trying to show that something
22
good happens, but the question has to be framed
130
1
within those two hemoglobin objectives, as I
2
understand it.
3
Am I clear in my thinking on the evidence
4
that exists?
5
DR. KEEGAN: I think you express
very well
6 the
same impression we have of the two trials that
7
showed a negative effect and the lack of
8
information we have in the other areas of
9
definitive information on the safety.
If the
10
companies want to show that there's a survival
11
advantage associated with their products, we have
12 no
problem with that. Our issue is really
that we
13
would like for them to definitively address whether
14 or
not there could be an adverse effect.
15
DR. CHESON: Dr. Brawley? Oh, excuse me.
16 Dr.
Brawley will defer for the moment.
17
DR. M. GEORGE: I just wanted to
follow up
18 on
the previous question and reiterate that the
19
clinical trial we are proposing is to assess the
20
activity on one single tumor trial using epoetin
21
alfa within the label, so in the anemic patient
22
population; and, lastly, that we're proposing a
131
1
non-inferiority trial, which explains why the trial
2 is
so large.
3
DR. CHESON: Thank you.
4
Dr. Brawley--or Dr. Parkinson first, and
5
then Dr. Brawley. Sorry, Otis.
6
DR. PARKINSON: Just relevant to
that is
7
that most of the trial results that I presented
8
here today were done with clinical trials during
9 the
development of Aranesp prior to development of
10 the
actual label. Our current
recommendations are
11
consistent, as I tried to make clear in the talk,
12
with the evidence-based guidelines, the
13
recommendations from ASH, from ASCO guidelines, and
14
from the NCCM guidelines and reflect current
15
practice.
16
Investigation of anything beyond that is a
17
matter for clinical trials and careful clinical
18
monitoring with carefully designed scientific
19
hypotheses. We would completely
support that.
20
DR. CHESON: Thank you. And now, Dr.
21
Brawley?
22
DR. BRAWLEY: Actually, this is
sort of in
132
1
follow-up to what Dr. Parkinson just said. My
2
understanding is that the current indication for
3
these drugs is for supportive anemia that is due to
4
either renal failure or due to chemotherapy. There
5 is
no claim in the package insert that these drugs
6
improve survival in any disease.
Correct?
7
DR. KEEGAN: That's correct.
8
DR. CHESON: Dr. George?
9
DR. GEORGE: I have a
question. It's in
10 the
Procrit area, I guess either for Dr. Bowers or
11 Dr.
George--a different Dr. George. That has
to do
12
with the endpoint chosen in the new study in that
13 you
chose progression-free survival even though in
14 the
study on which this was based, I guess, the
15
indication was--the problem seemed to be a
16
decrement in overall survival at 12 months and no
17
indication of any progression-free survival
18
problems.
19 DR. M. GEORGE: Overall survival is going
20 be
a secondary endpoint in the trial, and the
21
reason why we chose progression-free survival is as
22
follows: First, progression-free
survival is the
133
1
best way to assess if there's any effect--if there
2 is
effect, if any, on the tumor. Second, we
are
3
talking about a placebo-controlled trial so there
4
might be significant crossover if the tumor
5
progresses, if things change. So
that's one reason
6
after the crossover. The second
reason, which may
7
even more obscure the survival endpoint, is if the
8
patients fail the first-line chemotherapy, the
9
patients are going to cross over to another
10
regimen, and that may also obscure the survival
11
endpoint.
12
So we thought that carefully designed
13
progression-free survival endpoint--and, again, I
14
didn't go through the detail on how we are going to
15
assess it, how meticulously it's going to be
16
assessed, review by a blinded independent panel
17
will give us better enterprises.
And I'm just
18
reminded that we will have 80-percent power for a
19
non-inferiority trial in survival.
20
DR. CHESON: Dr. Feldman?
21
DR. FELDMAN: I'm just wondering,
are
22
there any data available or are there any trials
134
1
planned to address the issue of the use of
2
erythropoietin products in cancer patients not
3
receiving additional treatment?
4
DR. M. GEORGE: I'm going to
also--on
5
behalf of Johnson & Johnson, yes, we currently have
6 an
ongoing trial comparing placebo to Procrit in
7
patients who have cancer and are anemic and not
8
receiving chemotherapy. The study
is ongoing.
9
Survival is going to be assessed in that trial as
10
well as progression-related endpoints.
11 DR. CHESON: Dr. Parkinson, you should
12
just probably stand there.
13
[Laughter.]
14
DR. PARKINSON: Thank you,
Bruce. Yes, we
15
have ongoing trials in anemia of cancer patients
16 not
actively receiving chemotherapy. Again,
very
17
careful monitoring, data monitoring committees that
18 are
independent, all of that.
19
I'd like to point out also the particular
20
design of the AGO Study that I mentioned earlier.
21
Those are neoadjuvant patients.
They are biopsied,
22
therefore, prior to initiating chemotherapy, and
135
1
Aranesp therapy or not. And a
major endpoint of
2 the
trial is actually pathological endpoint at
3
surgery. So, in addition to the
status of the
4
tumor, there will be the opportunity to examine
5
carefully for any evidence whatsoever of
6
angiogenesis differentials between Aranesp and not.
7
I think it's a very powerful
design.
8
Investigators are very sophisticated and very aware
9 of
the importance of the biological results in
10
addition to the clinical results in this trial.
11
DR. CHESON: Don't go away. What are the
12
endpoints on the previous trials that you mentioned
13 in
the non-treated patients?
14
DR. PARKINSON: In the anemia of
cancer
15
trials, endpoints are predominantly anemia related,
16 but
follow-up is long term. Those trials
were
17
designed prior to any of these discussions, and--
18
DR. CHESON: Is it possible to
update the
19
statistics on those to look for survival?
20
DR. PARKINSON: Absolutely. I think that
21
there are a number of things that one may want to
22 do
at the end of the committee's deliberations and
136
1
recommendations. Absolutely.
2
DR. CHESON: Thank you.
3 Dr. Carpenter?
4
DR. CARPENTER: I just wanted to
comment
5 on
the survival endpoint in the previous study.
6
It's very hard to show a survival difference in
7
advanced breast cancer with any treatment. Even
8 though many people think certain things may
confer
9
survival benefit, it's hard to do a study large
10
enough and pure enough to find that because of the
11
large number of chemotherapy, hormonal, other, and
12 now
biological agents that are available. So
I
13
appreciate the company's diligence in trying to
14
sort that out, but I think their use of
15
disease-free of progression-free survival as a
16
primary endpoint is going to be a lot easier to
17
interpret and is going to be available a lot sooner
18
than trying to sort out what's going to be a
19
complicated bunch of information later.
20
DR. CHESON: I think what Dr.
George is
21
getting to is some consistency among trials with
22 enterprises
which, looking from the various trials,
137
1
there was some lack thereof.
2
DR. CARPENTER: Yes, but since
it's going
3 to
be done in breast cancer, that's going to be a
4
particularly hard thing to do.
5
DR. CHESON: Understood.
6
DR. CARPENTER: Where if it were
done in
7
some other tumor where there were many fewer
8
options for treatment later--and this is going to
9 be
done with first-line chemotherapy. It's
going
10 to
be a complex situation that might not be there
11 in
other tumors.
12
DR. CHESON: Thank you.
13
Dr. Redman?
14
DR. REDMAN: Just to follow up on
the
15
issue of the tumor-specific nature of the trials in
16
which there were negative signals, do the sponsors
17
have any plans to evaluate these agents in
18
non-solid tumors, in hematologic malignancies,
19
other than erythroleukemia?
20
DR. CHESON: Dr. Parkinson?
21
DR. PARKINSON: Yes, the GELA
trial, a
22
very large trial, 600 patients with aggressive
138
1
non-Hodgkin's lymphomas by a well-respected, very
2
accomplished, cooperative group in France, Belgium,
3 and
Switzerland.
4
DR. CHESON: Dr. Grillo-Lopez?
5
DR. GRILLO-LOPEZ: I wanted to add
to what
6 Dr.
Carpenter said, that an additional set of
7
confounding factors would be that in any randomized
8
trial where you have epoetin in one arm and not on
9 the
other arm, you are controlling for that during
10 the
course of the study. However, at some point
11
when those patients have a relapse and go on to
12
other chemotherapy, are you going to still require
13
that they do not receive epoetin ever during the
14
course of the remainder of their survival? I think
15
that would be very difficult to require, very
16
difficult to control and enforce.
So at some point
17 on
both arms, patients will be getting some of
18
these products, and I think that that's an
19
additional reason why overall survival is probably
20 not
an appropriate endpoint for these studies.
21
DR. CHESON: Good point.
22
Dr. Martino, did you have a question?
139
1
DR. MARTINO: A question to anyone
from
2
industry. Are there any known or
presumed clinical
3
parameters for which a hemoglobin above 12 is known
4 or
felt to be of value?
5
DR. DeLAP: Dr. Adrian Thomas of
our Drug
6
Safety Group will address that question for us.
7
DR. THOMAS: Adrian Thomas, Vice
8
President, Drug Safety Johnson & Johnson. I think
9 in
addressing that question, the benefits that have
10
been seen in the chronic renal failure population
11 with
erythropoietin therapy have generally been
12
seen at levels of hemoglobin less than or equal to
13
12. And one can postulate that by
increasing the
14
hemoglobin level by whatever mechanism, by having
15 an
effect on--a positive effect on the tumor, but I
16
think we've seen indications of positive effects on
17
tumor outcomes in some of our earlier studies at
18
hemoglobin levels more typically within the anemic
19
range that we would treat patients in clinical
20 practice. I don't think that we need to pursue
21
high-target hemoglobins to look for aggressive
22
outcomes.
140
1
I also want to make a point around the
2
concept of tumor-specific outcomes.
I think what
3
we've seen today is three very large meta-analyses
4 of
lots of tumors, and that, in fact, I'd challenge
5 the
word "tumor-specific." What we
have, in fact,
6
seen in terms of a biological signal is something
7
that isn't consistent with tumors.
We've seen no
8
effect on tumor response. We've
seen no effect on
9
tumor response. We've seen no
effect on tumor
10
progression. We have seen no
effect in our studies
11 of new target lesions. What we've seen is a
12
consistent signal both within oncology and from the
13
Besarab study of fatal outcomes linked to
14
high-target hemoglobins --[microphone off]-- need
15 to
be considered as a pharmacologically plausible
16
mechanism.
17
DR. CHESON: Dr. Demetri?
18
DR. DEMETRI: I'd like to make one
comment
19 as
a clinician who has done some of the studies on
20
also patient-reported quality of life where
21
patients have given data to support the benefits of
22 how
they feel in terms of better hemoglobin levels
141
1
beyond 12, interestingly, as well as some of the
2
preclinical evidence that might support better
3
oxygenation at higher levels.
Now, the latter is
4
more theoretical in terms of clinical outcomes, but
5
that was part of the rationale for the beyond
6
correction of anemia studies. And
I think that is
7 one key element to those investigational
8
strategies. But there are data in
the other
9
studies for supportive care for benefits at higher
10
levels.
11
DR. MARTINO: So are you saying,
then,
12
that we know from patient reports that self-reports
13 of
quality of life is somewhat better when a
14
hemoglobin above 12 is maintained?
I just want to
15 be
sure I'm understanding you.
16
DR. DEMETRI: I would say that is
correct
17
from the non-randomized large-scale studies that
18
I've conducted, my colleague Dr. Glaspy has
19
conducted, as well as others, yes.
20
DR. VIVEASH: Yes, I'd just like
to
21
comment that there's associative data in a number
22 of
disease settings, not necessarily in oncology,
142
1
that suggest higher hemoglobins are associated with
2
better outcomes. And, in fact, we
are going to be
3
doing some work in patients with chronic renal
4
insufficiency. I'd like to ask
Dr. Pfeffer to just
5
talk briefly about that program.
6
DR. CHESON: Briefly.
7
DR. PFEFFER: Thank you. So outside of
8
oncology, there are some indications that there is
9
real equipoise here and we need to do more
10
research. And as a matter of
fact, with the
11
burgeoning problems with diabetes and renal
12
insufficiency prior to dialysis, anemia is becoming
13 a
big factor, and the epidemiology suggests that
14
this is a comorbidity and co-risk.
So we're
15
undertaking, if I could just have one slide just to
16
show you the magnitude of the effort--no, that's
17
not--we're undertaking a 4,000-patient study of
18
people who are anemic, have diabetes, and who have
19
renal insufficiency, not in dialysis,. with very
20
hard cardiovasculars to determine if we can improve
21
their outcome. Obviously, with a
trial of 4,000
22
patients and over two years of follow-up, we'll
143
1
have a great deal of patient experience,
2
randomizing to a strategy to maintain the
3
hemoglobin to 13 or leave it where it is under 11.
4 So that's a strategy that's going forward,
so more
5
information is going to be forthcoming, and there
6
still is equipoise in the cardiovascular community.
7
DR. CHESON: Odd name for a trial
when
8
only half the patients actually get treated.
9
Ms. Mayer?
10
MS. MAYER: Just a comment on the
form of
11
reference to patient-reported responses to having
12
their hemoglobin level at a higher level. I wonder
13 how
those patients might respond if they knew that
14 by
doing so they might be increasing their risk for
15
thrombotic events. That might
color patient
16
perception.
17
DR. CHESON: Thus the need for
clear and
18
accurate informed consent.
19 MS. MAYER: Absolutely.
I would be
20
interested to know if in the informed consent in
21
that trial that was an issue that was explained to
22
patients, or if those findings of a higher risk for
144
1
those adverse events actually came from that trial.
2
DR. CHESON: Well, those are also
in the
3
package insert, but I would assume that they are in
4 the
informed consent.
5
One last comment from Dr. Keegan.
6
DR. KEEGAN: Actually, I did want
to put
7
into context the studies that Dr. Glaspy referred
8 on
quality of life were uncontrolled studies.
So
9
there was no way to put information in context.
10
The second is that he referred to patients
11 who
achieve hemoglobins above 12, and we would look
12 at
that as something of a responder analysis.
You
13
know, patients who do well do well.
I think that
14 one
should consider those single-arm studies with a
15
great deal of skepticism and caution given the
16
amount of missing information that's generally not
17
there from patients who were not doing well.
18
DR. CHESON: We will have additional
time
19 for
discussion during the discussion period.
Right
20 now
why don't we take a ten-minute break and
21
reconvene here at about 12 minutes of.
22
[Recess.]
145
1
DR. CHESON: We are ready to get
started.
2 Now
you can sit down, Dr. Parkinson.
3
[Laughter.]
4
DR. CHESON: The next part of this
session
5
involves the open public hearing.
No one has
6
approached us prior to this meeting to express an
7
interest in presenting. At this
point in time, is
8
there anybody who has shown up for this purpose and
9 has
not talked to us?
10
[No response.]
11
DR. CHESON: If not, then we will
move
12
into the committee discussion. I
just want to
13
reinforce, for those of you who are new to this,
14
that this is an Advisory Committee to the Food and
15
Drug Administration. We clearly
do not work for
16
them, but hopefully we work well with them.
17
We have been given a number of questions,
18
which are on a piece of paper that most of you got.
19 Dr.
Keegan has modified this to a minor extent.
20 Dr.
Keegan, would you just like to mention what
21
your modifications are?
22
DR. KEEGAN: It was just a
clarification
146
1 of
the concern that arose about placebo-controlled
2
trials, and I think the earlier wording might have
3 led
the committee and others to believe that it was
4 the
companies who felt that it was not feasible.
5 But
our understanding is that it isn't the
6
companies but physician investigators who have
7
raised feasibility concerns. So
we just reworded
8
that.
9
DR. CHESON: Clearly, from what we
heard
10
from the companies earlier, they feel it is
11
feasible.
12
We have a series of questions before us,
13
some of which are more compelling and some of which
14 are
less compelling, if the previous question is a
15
negative one.
16
We've already talked about the possible
17
reluctance of physicians to conduct and enroll
18
patients in placebo-controlled trials.
Do we have
19
some sentiment around the table here as to whether
20
this is a possibility? Dr.
Martino?
21
DR. MARTINO: I was just kind of
22
pondering. I wasn't ready to
answer. But since
147
1
you've asked, I think there will be physicians for
2
whom it will be an issue. You
watch a hemoglobin
3
going down, and you worry about--and I think to
4 some
degree physicians will be able to tell which
5
patients are in active therapy and which are not.
6 So
a placebo in this context is a relative placebo.
7 It
is not a placebo in the sense that there are no
8
clues of who is getting what. You
can't always
9
anticipate, you know, what that hemoglobin going
10
down or up is from. But, you
know, to a reasonable
11
degree I think there will be at least the
12
assumption that one knows what one's patient is on.
13
That being said, do I think
that there
14
will be physicians who will be willing and
15
unwilling to enroll in a placebo-controlled trial
16
asking these kinds of questions?
I think there
17
will be physicians in both of those camps, but I
18
think there will be enough who will recognize the
19
importance of the question, assuming the question
20 is
properly framed. And I'm not entirely
21
comfortable that I know that the questions have
22
been properly framed in the studies proposed. So I
148
1
have more of an issue with are the studies asking
2 the
questions that I consider of importance.
I'm
3
reasonably comfortable that there will be
4
physicians who will randomize.
5
DR. CHESON: Dr. Taylor?
6
DR. TAYLOR: I would agree. I think that
7
they're going to be looking at the other risks that
8
we're trying to elucidate, and they're going to be
9
willing to take those. And I
think some patients
10
will be more willing to take blood than Aranesp.
11
DR. CHESON: Dr. George?
12
DR. GEORGE: I don't have anything
to add
13 on
whether it's possible or not, except to state
14
that it would be desirable to do this if it is
15
practical.
16
DR. CHESON: Anybody else have any
17
comments on this? Dr. DeLap?
18
DR. DeLAP: I think our major
concern is
19
just we want to get studies done, and particularly
20
when we're looking at a 2,000-patient study, even
21
relative difficulties in accruing patients can be
22 an
issue, particularly in a disease like breast
149
1
cancer where the therapeutic regimens can change
2
over time.
3
The studies need to be done; they need to
4 be
done efficiently and relatively quickly.
And so
5 I
think we do still have some concerns in this
6
area, although I would agree it's not a complete
7
bar, but it is certainly an issue that has to be
8
considered in the design of these studies.
9
Could I just ask Dr. Cohen to speak on
10
this briefly?
11 DR. COHEN: I just want to speak as a
12
clinical investigator. I would
not underestimate
13 the
challenges of conducting placebo-controlled
14
trials. I would conduct them in
Europe and the
15
United States because, to echo one of the committee
16
members' comments, there will be investigators
17
falling into both camps.
18
Also, the way that the question is framed
19 is
absolutely critical. In order to get
patients
20 to
agree to be enrolled in these trials, I think we
21
have to postulate that there is a survival benefit
22 in
using these drugs. Of course, the trials
are
150
1
also powered to exclude a meaningful decrement in
2
survival.
3
And I think the trials will need to be
4
conducted by very mature clinical investigators
5
with meticulously written informed consents to
6
portray the issues accurately to the patients. But
7 they are feasible. There are unmistakable
8
challenges that will require a very prolonged and
9
multinational approach in order to get the job
10
done.
11
DR. CHESON: Dr. Martino?
12
DR. MARTINO: Patients are already
aware
13 of
the two trials that have brought this issue
14
forward, and those of us that practice oncology
15
have lots of patients who have called and written.
16 And
so it's not entirely an issue of placebo.
It
17 is
also an issue of patients knowing this newer
18
data who may not want to be randomized to the
19
treatment portion of this. So,
you know, it isn't
20
exclusively a placebo issue in my mind.
21
DR. COHEN: And I think in that
regard we
22
need to explain carefully to the patients what it
151
1 is
we're trying to do. We are trying to
treat
2
anemia. We are not going into
correction beyond
3
anemia. If we explain the issues
carefully to the
4
patients, they will be less afraid and more willing
5 to
participate.
6
DR. MARTINO: I need to pursue
this a
7
little bit more if you'll allow me.
Probably the
8
thing of greatest concern to me right now is it
9
appears to me that perhaps the real issue at gut
10
here is, in fact, the level of hemoglobin. That to
11 me
is a reasonable explanation to the discrepancy
12 in
the data. And with the exception of the
13
diabetic trial that was presented a few moments
14
ago, I have yet to see--perhaps I've missed it, but
15 I
have yet to see a trial in cancer that addresses
16
what I think may be the issue.
17
DR. CHESON: From the sponsors, is
there
18
such a trial that Dr. Martino is looking for that
19 has
been--
20
DR. DeLAP: Let me clarify the
issues that
21
you're trying to address here, whether there is an
22
expectation of a benefit in the anemic population
152
1
or--
2
DR. MARTINO: No. My question is: The
3 two
trials that have shown a tumor-specific
4
negative effect, okay? Both of
them dealt with
5 aiming
for a hemoglobin above, you know, the usual
6 12
or so, okay? That may be exactly the
issue.
7
That may be exactly the issue.
And if that is
8
exactly the issue, then the proposed trials aren't
9
addressing that. And you could be
doing all kinds
10 of
things and never getting at the issue.
11
DR. DeLAP: You're correct in that
there
12 is
the one trial that addresses the target
13
hemoglobin level prospectively.
That was the
14
Normal Hematocrit Trial, which was in renal
15
patients, not in cancer patients.
We do not have a
16
trial randomizing patients to different target
17
hemoglobin levels.
18
We do have--actually, if I could just call
19 up
our slide DE3, I think it is. We do have
one
20
experience in our clinical trials program that I
21
think speaks to this, which is one of trials where
22 we
have the biggest issue with these TVE events and
153
1
possibly some survival impact is this small-cell
2
lung cancer trial which was terminated prematurely,
3
again, for TVEs.
4
Now, the interesting thing about this
5
trial is that, as originally designed, the patients
6
were treated to a target hemoglobin of 14 to 16.
7 In
October 2002, for reasons unrelated to looking
8 at
any data but just that that seemed to be too
9
high of a target, the target was modified to 12 to
10
14. Patients were randomized both
before and after
11 the
amendment. Patients were treated for
similar
12
durations with erythropoietin therapy both before
13 and
after the amendment. And yet you can see
that
14 in
the pre-amendment group, although the numbers
15 are
small, in the pre-amendment group 42 percent of
16 the
patients in the erythropoietin alfa arm had
17
these TVE events. And in the
post-amendment group
18
treating to the lower target--which is still a
19
higher target than we might like to use now, but,
20
clearly, at the post-amendment point, it was 10.5
21
percent. So that's suggestive
evidence, at least
22 in
a cancer population, that we're following the
154
1
right path by treating to a lower hemoglobin
2
target.
3
DR. CHESON: Do you have any
information
4 on
what the median hemoglobin was that was attained
5 in
the two arms--not in the two arms but in the two
6
patient populations?
7
DR. DeLAP: Let me refer that to
Dr.
8
Adrian Thomas, who has more details about that
9
study.
10
DR. THOMAS: I think this is
certainly an
11
interesting question. What we
observed
12
pre-amendment is, in fact, that the hemoglobins in
13 the
patients who developed TVEs were around the 15
14
level, and following the amendment the hemoglobins
15
were around the 12 to 13 level.
And so I think we
16 can
see, although not pre-defined, we can see some
17
empiric evidence of the effect of changing the
18
target hemoglobin level.
19
DR. CHESON: Dr. Parkinson?
20
DR. PARKINSON: Just a comment
that, as I
21
indicated earlier, the clinical trial results that
22 I
demonstrated were, in fact, conducted with trials
155
1
that took patients to target hemoglobins of 13.
2
That doesn't reflect the current practice, but
3
that's, in fact, what was the operative practice
4
during the conduct of those trials.
There are
5
other reasons to go higher, which we could get
6
into. Professor Overgaard is
here, and he spoke to
7 me
at the break about the rationales for doing
8
that. But I think that's not
where you're coming
9
from, Dr. Martino. Is that
correct?
10
DR. MARTINO: I'm trying to figure
out
11
what the real question is that we want to answer
12 here,
and I guess one of the questions is: If
you
13 aim
for 12, or thereabouts, is there an effect on
14
tumor biology, survival, whatever endpoint you want
15 to
look at? And that's a very worthwhile
question.
16
DR. PARKINSON: Okay. In that case, could
17 I
call upon Professor Overgaard, who is here from
18 the
Danish Head and Neck Cancer Study Group
19
someplace? He told me he--oh,
there he is. How
20
could I miss you?
21
DR. OVERGAARD: My name is Jens
Overgaard.
22 I
come from Denmark. The reason for this
was that
156
1
earlier, before the break, there was a question as
2 to
what are the rationales for having a survival
3
benefit of these trials here, and it was said that
4
there were plenty. But it is
fairly simple,
5
basically, because this is a matter of oxygen
6
delivery. And we must assume that
what we really
7
would like to have is more oxygen brought forward
8 by
more hemoglobin into the tumor. And that
oxygen
9
should do something in benefit for outcome. That
10
means it should interact with the treatment, which
11
will be better in one way or another if there is
12
more oxygen delivered. And what
you said, people
13
know that might be very well the case because
14
hypoxia is a key issue in the response to
15
radiotherapy.
16
Now, if that treatment will be better
17
issued in turn also influence the survival in the
18
(?) , these are the fundamental
simplicity of the
19
design of the rationale. In such
studies and the
20 one
we are doing in radiotherapy, it is a matter of
21
lifting oxygen delivery from one level to a higher
22
level. It is not a matter of
lifting to some
157
1
specific level of 12 or whatever.
It's just a
2
matter of having a differential.
And the only
3
thing that puts a limit on that differential is the
4
ceiling. So what we have to
discuss here is more
5
where is the ceiling, where is it halfway up to the
6
ceiling, because we need to have the room for
7
excess oxygen delivery if we have to do survival
8
benefit trials.
9
DR. CHESON: Dr. Keegan?
10
DR. KEEGAN: Dr. Martino, is your
11
question--and I think it's our question, too--that
12 if
studies are done using a higher hemoglobin,
13
permitting or encouraging a higher hemoglobin
14
target and they show that there is, in fact, a
15
detrimental effect, we will have no information on
16
whether or not at the approved dose and for the
17
intended and licensed indication, which is
18
avoidance of blood transfusion, whether or not
19
these are safe? And so by not
starting first at
20 the
approved dose and schedule and in the currently
21
indicated population we may be actually prolonging
22 our
time to getting an answer?
158
1
DR. MARTINO: In the ideal world,
what I'd
2
like to see is both of these hemoglobin dose levels
3
addressed and in each of those, the same question
4
asked: Is it good? Is it bad?
5
Now, that's what I'd like in the ideal
6
world. I do recognize that
there's another issue
7
here, which is a trade-off in the sense that it
8
already is fairly apparent that there are more
9
complications as you increase the level.
So you
10 get
to this issue of, you know, relative good and
11
relative bad. But it really is
each of those
12
levels which are of concern to me.
13
DR. VIVEASH: Could I just
comment? I
14
decided I'd give Dr. Parkinson a break for a
15
moment.
16
He presented a number of studies,
17
forward-looking studies, some of which are ongoing.
18 The
vast majority of those are actually using the
19 current
label target hemoglobin so we'll address
20 the
one question. The DAHANCA Study actually
goes
21 to
a higher hemoglobin, and we feel both approaches
22 are
valid as long the studies are appropriately
159
1
conducted with the appropriate endpoints and
2
appropriate safety monitoring.
3
DR. CHESON: Thank you.
4
Dr. Redman?
5
DR. REDMAN: This is regarding
6
randomization, especially to Amgen and the European
7
studies. Your target hemoglobin
is somewhere
8
between 13 and 14, it sounds, in most of the
9
studies--the small-cell, the breast.
I don't know
10
what the policy is or what the benefit is in
11
Europe. In the United States, the
blood bank will
12 not
release blood for a hemoglobin of 13 unless the
13
patient is actively bleeding. So
how are you
14
controlling for the transfusions in those?
15
DR. PARKINSON: These are not
16
hemoglobin-controlled trials.
These are trials of
17
Aranesp to specified levels versus transfusions as
18
used in regular clinical medicine.
That will
19
differ in different settings.
20
DR. CHESON: Are there any more
comments?
21 Ms.
Mayer?
22
MS. MAYER: I'd like to return to
the
160
1
issue of accrual to randomized trials.
I have some
2
concerns that patients may have difficulty
3
submitting themselves to randomization, whether or
4 not
they're randomized to either arm, actually,
5
because I think patients tend to come to their own
6
conclusions in situations where it's really unclear
7 and
where there are complex risk/benefit ratios
8
like the ones we're discussing.
And in those
9
situations, I think patients like to have choice.
10 You
know, given that this is on the market, some
11 may
choose to have transfusions and to avoid EPO
12
until these issues are resolved, while others may
13
decide it's a reasonable risk to take.
14
But the real question is: Will
they be
15
willing to be randomly assigned?
And I think that
16
will be also mediated by the kind of media coverage
17
this gets and how it's presented to them. It's a
18
really problematic issue because the drug is out
19
there.
20
DR. CHESON: Okay. If we could summarize
21 the
first question, which boils down to: Is
it
22
reasonable to request that placebo-controlled
161
1
trials be conducted to assess the risks of or rule
2 out
a negative effect of EPO on time to progression
3 and
survival? And my feeling is that we all
feel
4
that it's not only reasonable but it's probably
5
essential. Is that the sense of
the committee?
6
VOICES: Yes.
7
DR. CHESON: Antonio?
8
DR. GRILLO-LOPEZ: Perhaps with the
9
exception noted earlier in our discussion that
10
overall survival may not be the best endpoint, but
11
time to progression or progression-free survival
12
could do it.
13
DR. CHESON: Okay. Dr. Redman?
14
DR. REDMAN: I'm sorry. The question
15
between time to progression versus survival, is
16
that what you're asking? Or
just--
17
DR. CHESON: No, I was asking the
concept
18
of--I wasn't asking. I was
summarizing the concept
19 of
doing the randomized controlled trial, whatever
20 the
endpoint we decide to be, is not just
21
reasonable but is necessary.
22
DR. REDMAN: Yes, okay.
162
1
DR. CHESON: Now, as far as the
endpoint,
2 as
we are going to be discussing this afternoon and
3
have discussed in the past, this endpoint may
4
differ from tumor type to tumor type.
And there
5 are
pros and cons, as we've heard passionately from
6 Dr.
Grillo-Lopez, about one endpoint versus
7
another, PFS versus overall survival.
And Dr.
8
Carpenter made that point also in breast cancer.
9 It
sounds like progression-free survival is
10
probably a better endpoint.
11
Can we do this trial in the U.S.?
The
12
second part of this. And I think
we heard from our
13
patient advocate that it might be difficult, but I
14
think we also heard from the sponsors that these
15
trials are accruing, and hopefully they will
16
succeed. So I think the answer to
that one is
17
probably also the--
18
DR. DeLAP: Could I ask Dr. George
to --
19
[off microphone].
20
DR. CHESON: Please.
21
DR. M. GEORGE: If I have the
chance to
22
comment on accruing patients in the U.S., if I
163
1
think it's feasible, it's feasible.
How feasible
2 it
is, that's the real question, because we want to
3
have the answer to the question really, really fast
4 and
not wait. So we can have a trial up and
5
enrolling patients in a placebo-controlled trial
6
(?) period of time and wait for
the answer or do
7 it
in a different way and including patients
8
outside of the U.S. So the
primary reason to the
9
trial outside of the U.S. is speed.
10
DR. CHESON: Ms. Mayer?
11
MS. MAYER: I have some concerns,
I guess,
12
about our making use of patient populations outside
13 the
United States to avoid the ethical issues that
14 may
arise in doing trials here. It has to do
with
15
disclosure, I suppose, and how patients interact
16
with their health care systems. I
don't think it's
17 a
simple issue that we should just glide right over
18 and
say, yes, do the trials abroad.
19
DR. DeLAP: We're very sensitive
to these
20
ethical issues and, in fact, it's certainly the
21
company's position--I'm sure it's also the position
22 of
Amgen--we will not pursue a study in a
164
1
particular region because, you know, there are
2
ethical questions. It has to be a
fully ethical
3 and
well-justified trial wherever it's done.
4
DR. CHESON: Dr. George--
5
MS. MAYER: Can I do a follow-up
on that?
6 I
just want to point out that in countries where
7 the
blood supply is not as safe as it is in the
8
United States, this may be a particular issue.
9
DR. PARKINSON: Just a
comment. We work
10
globally. Cancer is a global
problem. It is
11
solved by global cooperation. We
work under the
12
same rules globally, just as Dr. DeLap emphasized,
13
same kinds of informed consent, same practice. We
14
would not work in a place where those kinds of
15
parameters were not in equipoise.
16
And with respect to the
ability to work in
17 the
United States, as we heard, with mature
18
investigators who can ask questions responsibly,
19
even in the placebo-controlled setting, I just
20
wanted to re-emphasize we've just accrued 145
21
patients over three weeks to a placebo-controlled
22
study of Aranesp in chemotherapy-induced anemia.
165
1 Is
it as--no, it isn't as easy, of course.
It's
2 never
as easy in a randomized trial as it is in a
3
single-arm trial. And it's never
as easy in a
4
randomized trial when there's a placebo control.
5 But
sometimes it's actually necessary to
6
adequately--and we believe our responsibility is to
7
answer these questions definitively.
We believe
8
patients have been confused by the reports of these
9
studies, and we believe that it's our
10
responsibility to them to answer this.
11
DR. DeLAP: To the extent that
we're
12
looking at a more homogeneous population, we've
13
certainly done a lot of placebo-controlled trials
14 in
chemotherapy-induced anemia or in
15
non-chemotherapy-induced anemia in cancer patients,
16
we're studying that also in the U.S. in
17
placebo-controlled trials. But
when you start
18
focusing in on a specific population with a lot of
19
criteria to get as homogeneous a population as
20
possible, you can't cast as broad a net as you can
21 for
chemotherapy-induced anemia.
22
Again, we're just saying--I think we're
166
1 all
saying the same thing, but practicality demands
2
that if we're going to do this kind of work
3
efficiently, it has to be global.
4
DR. CHESON: Dr. George?
5
DR. GEORGE: I just wanted to
clarify one
6
thing. The FDA can correct me if
I'm wrong, but
7
there is nothing in the regulations or guidelines
8
that prohibit exclusive use of, in fact, foreign
9
data, if you want to call it that, in proving
10
things, right? That's one point.
11
DR. KEEGAN: Yes, that's correct.
12
DR. GEORGE: But with respect to
that
13
little broader issue, it's certainly the case that
14
medical practices and cultures differ in countries
15
that would make it possible or more likely that you
16
would enter more patients from one country than
17
another. That's inevitable. And I don't think
18
that has anything to do with ethics unless you
19
believe there's some kind of universal ethics that
20
doesn't--you know, that applies to all countries,
21
which I think, you know, with respect to equipoise,
22 is
not really true. That is, it's been
shown in
167
1
other studies that the Europeans are more skeptical
2 of
certain kinds of things that maybe we do, and
3 vice
versa. So it doesn't bother me, as long
as,
4 as
Dr. Parkinson says, you're dealing in an area
5
that's accepted all the usual rules and
6
regulations.
7
DR. WEISS: If I can just add,
it's also
8
just an issue of whether or not you can generalize,
9 as
we've had some discussions, the results
10
across--you know, overseas to U.S. populations and
11
whether or not there are significant differences in
12
practices that would make those results somehow not
13
applicable.
14
DR. CHESON: Well, obviously,
there are
15
some agents which will require some pharmacogenomic
16
differences, as we heard back last year with one
17
particular drug that was more effective in one
18 country
than in another. But, in general, this
19
shouldn't be that big a problem.
20
Dr. Martino?
21
DR. MARTINO: I want to deal a
little bit
22
with the issue of whether data which is generated
168
1 in
Europe or elsewhere is accepted in this country.
2 You
know, we have a very mixed history in this
3
country of what we accept that isn't generated
4
here.
5
Now, there are things that the companies
6
themselves can do to either enhance this separation
7 or
to not allow the separation. And so I
just want
8 to
remind them that when their data is summarized
9 and
presented, whatever the results are, it becomes
10
critical to present the data as it is meant, which
11 is
one study done internationally.
Oftentimes with
12
large studies, especially when the results aren't
13
exactly what you had hoped for, there's a tendency
14 to
then separate the American group and its
15
results, the European group and its results, and
16
they're not always concordant.
17
And so there are ways to actually either
18
accentuate the American desire to not accept
19
non-American results, depending on how one handles
20 the
presentation of these data.
21
DR. CHESON: Point well taken.
22
Dr. Keegan?
169
1
DR. KEEGAN: Just one last comment
about
2 the
European data. Dr. Weiss has summarized
pretty
3
much our position on that. But
one nuance here is
4
that Procrit is not approved or not marketed in
5
Europe. So if there was a study
either that had
6
European sites or a separate European study, it
7
might be conducted with EPREX rather than Procrit.
8
We've already taken the position that these are
9
class effects, to some extent, and we think it
10
would at least address questions in the class.
11
Would the conduct of a study in which certain
12
patients received a related product in the class
13
different in Europe than in the U.S. pose problems,
14 or
for instance, if the study was conducted
15
entirely in Europe, the data were obtained with
16
EPREX, would that be problematic, do you think, to
17 the
committee in looking at--
18
DR. CHESON: Well, the reason
we're here
19 is
two studies conducted with a different product
20 that's
caused a flurry in this country. So I
think
21 the
opposite would probably hold true. If
those
22
studies had not shown this potential problem, we
170
1
wouldn't be sitting here today.
2
So I personally would find these very
3
similar compounds, the data from them to be
4
applicable on both sides of the puddle.
5
Dr. Feldman?
6
DR. FELDMAN: Just one very brief
comment,
7
made perhaps out of the naivete of a non-clinician,
8 but
I was a little bit concerned by the comments of
9
using European studies because it could be done
10
faster. I don't think the speed
of getting the
11
answer should really be an issue here.
I think the
12
idea is to get the best answer and most complete
13
answer to the questions.
14
DR. DeLAP: At J&J we agree
with that,
15
that speed per se is not the issue.
Getting the
16
best answer in a reasonable period of time is. But
17
there is some interrelationship because there are
18
changes, for example, in breast cancer them
19
regimens. So if you're trying to
have a study that
20 has
a relatively homogeneous approach to the
21
treatment of patients, and then that study turns
22 out
extending out for six or seven years, it may
171
1
impact the quality of the study.
Also, I think
2
there is a strong desire to address this question
3 as
promptly as we can. Again, speed at all
costs,
4
no. But speed to get a good
answer, yes.
5
DR. CHESON: Dr. Redman?
6
DR. REDMAN: I just want to make a
comment
7 about
speed. As a clinician, I think if the
trial
8 is
adhered to, the quicker the accrual goes to the
9
trial, it is best. Speed does not
imply a bad
10
trial.
11
DR. CHESON: Dr. Reaman?
12
DR. REAMAN: I would echo the
comment on
13
speed. But for clarification, are
we talking that
14
trials will either be done in Europe or in the
15
United States? Or if this really
is a global
16
initiative, would they be international trials?
17
DR. CHESON: To finish my summary
of this
18
before moving on to the next question, yes, these
19
trials are necessary, and I think the studies are
20
ongoing on both sides of the ocean, and that's how
21
they should be done. And
hopefully they will be
22
completed alacrity in both situations.
172
1
Now, I think we already got to the other
2
question, that if there are so many variables
3
affecting response rate, survival, and safety, the
4
tumor type, et cetera, et cetera, if you had one
5
large trial that we all agreed on the endpoints,
6
that was conclusive in one disease, since we are
7 all
here considering homogeneity of patients, would
8
that one trial answer the question for all
9
diseases? Or do we require now
multiple trials in
10
different tumor types?
11
I personally feel that if we can answer it
12 in
one very nice, well-done study in a common solid
13
tumor, that would answer it for me.
Dr. Martino?
14
DR. MARTINO: But it seems to me
that the
15
companies have already made these decisions, that,
16 in
fact, they are doing several trials in different
17 tumors,
and I have to say enough time has passed
18
that I only remember a few of the studies.
19
And so I would be really happy if someone
20
would succinctly review those trials because I
21
thought what was wanted from us was our thoughts as
22 to
whether these trials were good, bad, or
173
1
indifferent.
2
Now, granted that they're already in
3
progress, perhaps my views on any of them are
4
irrelevant.
5
DR. CHESON: Could you state your
name and
6
affiliation, please?
7
[Laughter.]
8
DR. PARKINSON: Well, just to
remind you
9
about the clinical trials that we discussed, the
10
first is an Amgen-sponsored trial in small-cell
11
lung cancer, and 213 patients of the anticipated
12 600
patients have been accrued. That's
13
placebo-controlled.
14
The next trial is the AGO trial that I
15
talked about. That's a
neoadjuvant breast cancer
16
trial being conducted by the German Gynecologic
17
Oncology Study Group. That's a
study with an
18
anticipated enrollment of around 700 patients, a
19
little more than that, of whom 400 patients have
20
already been accrued. I indicated
that that
21
interim analysis, which will include pathology
22
endpoints, will be looked at by the Data Monitoring
174
1 and
Safety Committee in approximately five or six
2
weeks.
3
The third study is a study by the Western
4
German Study Group, and they'll be studying
5
adjuvant breast cancer patients, and that trial has
6
just started accrual.
7
The fourth study, the GELA Study, is a
8
study in aggressive non-Hodgkin's lymphoma--oh,
9
there it is. Thank you. I was doing this by
10
memory. This is so much easier,
actually. The
11
GELA group is studying patients with non-Hodgkin's
12
lymphoma randomized to either dose stance or
13
standard chemotherapy plus or minus Aranesp or no
14
epoetin.
15
And then the final study is being
16
conducted by the Danish Head and Neck Cancer Study
17
Group. You've heard already this
afternoon from
18 Dr.
Overgaard about the rationale for that study
19 and
the fact I've indicated here that 260 of the
20 600
patients have been already accrued, with a
21
safety interim analysis already completed and the
22
study continuing.
175
1
DR. DeLAP: If we can just quickly
come
2
back to the slide from Dr. George's presentation.
3
DR. M. GEORGE: Thank you. This is a
4
slide I showed you earlier in four separate tumor
5
types where we have ongoing or completed clinical
6
trials where a tumor-relevant endpoint is the
7
endpoint.
8
We have many other trials, some very, very
9
large, including thousands of patients, in tumor
10
types like breast cancer, adjuvant breast cancer,
11 or
Hodgkin's disease. Those trials enrolled
1,000
12
patients, but are not geared toward survival but
13
assessing correcting anemia and quality of life.
14 So
I'm not going to present any of those trials,
15 but
the list very, very lengthy.
16
In the tumor type, where we have relevant
17
endpoints are head and neck cancer.
The (?) of
18 the
seven(?) trials has enrolled, is completed, has
19
enrolled 301 patients, is currently under
20
follow-up, and the primary endpoint is disease-free
21
survival at two years. We will
have those data
22
very, very shortly.
176
1
The RTOG study is a study in patients also
2
receiving radiation therapy for advanced head and
3
neck cancer. The study started
with radiation
4
therapy alone, then was amended to include
5
chemotherapy also.
6
As mentioned earlier in Dr. Bowers'
7
presentation, the study was stopped to accrual
8
because of the increased incidence of TVE. And
9
when the Data Safety Monitoring Board of the study
10
reviewed the interim data, they thought that in
11
their trial there was no possibility of showing a
12
benefit. Those patients are in
follow-up, and we
13
will have the data shortly
14
In non-small-cell lung cancer, there is a
15
pretty large study in Germany called GER-22, which
16 is
planned to enroll 612 patients. Current
17
enrollment is around 250 patients, and the study is
18
ongoing. The last Data Safety
Monitoring Board
19
meeting was a few weeks ago, and the trial is still
20
ongoing. The patients received
chemotherapy first,
21
followed, after three cycles of chemotherapy, by
22
radiation therapy. The patients
who have locally
177
1
advanced Stage III untreated non-small-cell lung
2
cancer--
3
DR. CHESON: We're going to need
to limit
4 the
details on this, because the point was:
Do we
5
need more than one trial? And
it's quite obvious
6
from both of these slides that we already have
7
many, many trials going on.
8
DR. M. GEORGE: And we're
proposing a
9
large trial on top of all those trials.
10
DR. CHESON: Thank you.
11
DR. KEEGAN: Dr. Martino, just to
clarify
12 the
sequence of events, as we became aware of this
13
data, we contacted the companies to determine what
14
studies they had available or planned that might
15
speak to this question. But the
purpose of this
16
committee is to comment on the qualities of such
17
trials that you think should be incorporated to
18
provide convincing data. So that
if, in fact,
19
although they have many trials that are in the
20 works or ongoing, if you find that they are
lacking
21
critical elements, we would like to hear that so
22
that we can negotiate with the companies the
178
1
appropriate trial to get the data.
So that if you
2 see
that there are critical elements missing,
3
that's really why we need to talk about this. They
4 may
have studies going, they weren't intended for
5 the
purpose we are here to discuss today, but they
6 may
fit the bill. If they don't, we would
like you
7 to
say so.
8
DR. CHESON: Clearly, we haven't
seen the
9
protocols, but based on what we've seen in the way
10 of
presentations, there are quite a number of
11 studies for which the primary endpoint are
those
12
that the FDA is looking for. They
are accruing
13
patients, and so from my perspective hopefully at
14
least several of these out of the very large number
15
will be addressing the important issues that have
16
brought us here today.
17
First will be Dr. Redman.
18
DR. REDMAN: I agree with Dr.
Cheson. The
19
studies are ongoing. In order to
analyze a study
20
based on one slide is next to impossible. It lacks
21 a
lot of information. But I think looking
at the
22
companies that are doing those trials and the
179
1
investigators that are doing them, I certainly
2 don't have a problem with what's been going
on.
3
DR. CHESON: If you'd like us to
look at
4
some of these protocols with you and make sure they
5
have the appropriate elements, we'd be glad to do
6
that in our advisory capacity.
7
DR. WEISS: I'm just wondering
if--Dr.
8
Martino started this discussion earlier on about
9 the
issue of whether or not you should study a
10
population--everybody agrees, I think, that a
11
homogeneous population is important, but whether
12 you
should try to address the issue if you have a
13
target hemoglobin of sort of the standard range
14
that's in the label, which is approximately 12 or
15 so,
versus a strategy of pushing to the higher
16 hemoglobins. It seems like there's some diversity
17 of
opinion around the table about what are the
18
important questions or how the study is to be
19
designed, what should be the strategy in terms of
20 the
targets. And just looking at the slides
that
21 Dr.
Parkinson presented where they summarized on
22 the
slides what the targets were, there were a
180
1
number of them that basically strove for a target
2 of
about 14. Obviously, it's a little bit
3
different, I guess, if you're talking about men
4
versus women and what trials.
But, in general,
5
you're talking about 14 except for the one Danish
6
trial which would be achieving a target of 15 or
7
pushing to try to, I guess, taper or stop the dose
8 if
the hemoglobin goes to 15.
9
We didn't really hear from Dr. George
10
about what the targets where in those numbers of
11
different ongoing trials. So I'm
just wondering if
12
those--except that the one that they're proposing
13 to
do in breast cancer, which is actually designed
14 to
target a hemoglobin that actually is at the
15
recommended label of hemoglobin, which is about 12
16 or
so.
17
So I'm just wondering--I mean, it seems
18
like there's a smattering of many different trials
19 and
many different tumor types, some looking at a
20
target of one versus a higher target.
There's sort
21 of
a whole hodgepodge of things, but is there a
22
particular issue with respect to target that--I
181
1
guess I'd like to hear from the committee whether
2 or
not there's a particular target that we should
3
really be asking the companies to look at in terms
4 of
the strategy in terms of trying to assess
5
benefits and risks.
6
DR. CHESON: Dr. Parkinson, a
quick
7
answer.
8
DR. PARKINSON: Just one quick
9
clarification, for the five trials our target of
10 13,
okay? Hemoglobin, withheld if above that
at
11
14. That's European label, so
that's guidelines in
12
Europe. The fifth trial is the
Danish trial. Just
13 a clarification.
14
DR. THOMAS: As a further point of
15
clarification, we have amended all ongoing
16
protocols in this area to reduce the target
17
hemoglobin levels to a uniform level, and our view
18
would be that to do one at a higher level is to do
19 a
study on TVE, not on benefits in terms of tumor
20
responses.
21
DR. WEISS: I guess it goes back
to
22
something that Dr. Martino raised earlier, which is
182
1
that many of these studies, with the exception of
2
just a few minor ones, are actually now tapered
3
down to looking at outcomes within the recommended
4
label target. Whether or not
that--you know,
5 whether or not you have comments about that,
6
because I know you raised that issue earlier,
7
whether that's something that should actually be on
8 the
table to consider. If there are no
issues at
9
those targets, is it appropriate to try to push to
10
higher targets to evaluate potentially other
11
benefits in terms of better survival and other
12
outcomes?
13
DR. CHESON: Dr. George was next.
14
DR. GEORGE: Well, my comments
weren't
15 directly
related to that.
16
DR. CHESON: We want to finish
this first.
17
Do you have a comment related to this?
18
DR. CARPENTER: It would seem at
least
19
logical to me to approach the question about tumor
20
benefit or risk at the levels currently targeted
21
now. If we then find either some
beneficial effect
22 or
at least exclude a detrimental effect, that
183
1
would leave the table open to go to a separate
2
study that compares two levels.
But it seems to me
3
that if we try to answer the two questions at the
4
same time, we're going to get numbers problems.
5
We're going to get problems with speed of accrual
6
that are going to make it harder to get a timely
7
answer to the first question.
8
DR. CHESON: I agree with
you. It's my
9
feeling that we would first like to have our level
10 of
comfort at the indicated dose of the drug that
11 it
was safe and efficacious. If there are
12
questions, such as the head and neck study we've
13
heard about, of higher doses, then those are
14
investigational doses that can be explored
15
separately. But I'd be willing to
hear from my
16
colleagues if they disagree or agree.
17
Dr. Reaman?
18
DR. REAMAN: I absolutely agree,
and I
19
think if we're going to be looking at safety at the
20
currently recommended indication, then we really
21
ought to consider excluding those trials in which
22
there is a target higher than what is the indicated
184
1
target in the package insert.
2
DR. CHESON: Any other comments on
this
3
particular point?
4
[No response.]
5
DR. CHESON: Then we go to Dr.
George.
6
DR. GEORGE: Well, the point I was
going
7 to
make was in reference to these issues of the
8
design. And it has to do with
making sure that
9
what we're really trying to do is eliminate a
10
detrimental effect of some magnitude, I think. And
11
that can be done in studies; even when it's some
12
kind of superiority design, you can still make sure
13
you're looking at things that--because some of the
14
trials that even were presented showed--they were
15
presented as if there was no difference.
But, in
16
fact, if you look at things just as simple as the
17
confidence intervals on certain things like hazard
18
ratios, they didn't exclude something that might
19
have been pretty detrimental, even though the
20
curves were superimposable and looked exactly the
21
same. That's the problem with
these
22
non-inferiority kinds of designs.
185
1
But I think we have to keep that in mind,
2
that that's really what we're after here. I mean,
3 if it
works, great. But what we're trying to
do is
4
make sure it's not something bad.
5
DR. CHESON: Ms. Mayer?
6
MS. MAYER: Perhaps I missed one
of the
7
trials, but the BEST Trial was done in first-line
8
metastatic breast cancer. The
proposed two breast
9
cancer trials I believe are both adjuvant trials.
10
My question is: Is there a
concern that
11 you
might not in adjuvant trials capture the same
12
effect that appeared perhaps in the metastatic
13
trial?
14
DR. M. GEORGE: If I may try to
answer
15
your question, the proposed trial is not a trial in
16
adjuvant breast cancer, but it's to treat patients
17 who
have metastatic disease. There are some major
18
differences between the BEST Trial and the proposed
19
trial. The first one is the
patients are anemic at
20
entry. The second is how we are
going to assess
21
endpoint. The third one is the
duration of therapy
22
with erythropoietin. In the BEST
Trial, the
186
1
duration of therapy was one year targeting high
2
hemoglobin level.
3
DR. CHESON: Thank you.
4
Dr. Taylor?
5
DR. TAYLOR: I want to support the
idea
6
that we are looking at more than one tumor because
7 I
don't think we do know exactly why people may do
8
worse. I don't think we have an
etiology or a
9
mechanism for which the erythropoietin product may
10 be
adversely affecting people. So I think
that
11
looking at different populations is not a bad idea.
12
The other reason is that extrapolations
13 are
already made in that a lot of women receiving
14
adjuvant chemotherapy are on erythropoietin
15
products, and we need to know is it just the fact
16
that a woman has metastatic disease, is sicker, and
17 has
other predisposing factors, or is it
18
erythropoietin?
19
DR. CHESON: Okay. Well, that question
20 has
answered itself in that we have so many trials
21
going on in so many diseases.
22
Dr. Bauer?
187
1
DR. BAUER: I think there's a
fairly
2
narrow margin here, especially from the safety. I
3
think the clear thread is that, you know, you drive
4
hematocrits up higher and you get more thrombogenicity. And
5 so
I think, you know, the trials, I
6
guess, we're all talking better built in with
7
hemoglobin limits which are lower than those that
8
might have been desired, say in some of the
9
radiotherapy trials to improve oxygenation,
10
especially when you're talking about trials where
11
you're entering people who will probably have
12
normal hematocrits who would normally not be
13
candidates for erythropoietic growth factor. Your
14
margin in terms of driving up hematocrit is not all
15
that great.
16
But I think in response to the query, I
17
think you have to have clear limits in terms of
18
keeping hemoglobin either below 14 or certainly
19
target 13 and stop, or something, for patient
20
safety, for protection, because you just don't want
21
hematocrits to go uncontrollably high.
22
DR. CHESON: Okay. So, to summarize the
188
1
answer to this question, there really is no need to
2
summarize this because we already have multiple
3
trials going on. And if you have
concerns about
4 the
specifics of the trials, I'm sure you have the
5
protocols, and if you need some of us to go over
6
them in our particular areas of expertise, I'm sure
7 my
colleagues would be glad to do that.
8
The next point I think we discussed a
9
little bit earlier, but maybe not conclusively, and
10
that is, the FDA has recommended that trials be
11
conducted in primary tumors where the EPO-R status,
12
whether it be expression, ligand, affinity, and
13
functionality of malignant cells in tumor
14
vasculature is known.
15
That's going to be tough. I think
we
16
heard some very eloquent information this morning
17
that, A, it's going to be difficult and, B, it may
18 not
be totally relevant, but I'm opening the floor
19 to
additional discussion as to whether this
20
is--it's a nice idea, but is it doable in a variety
21 of
circumstances? Feasibility,
technicality, and
22 is
it really relevant? Dr. Doroshow?
189
1
DR. DOROSHOW: Yes, I think that
although
2 I'm
usually a proponent of obtaining fresh frozen
3
materials for correlative studies, I think that
4
this is not feasible other than in the neoadjuvant
5
setting. I think the trials are
of such size that
6 at
most you will get a very small fraction that
7
will be potentially not reflective of the outcomes
8
you're trying to study. That's
even irrespective
9 of
the elegant data that we were presented with
10
earlier about lack of relevance.
11
DR. CHESON: Okay. So does anybody else
12
want to comment on--could you please identify
13
yourself?
14
DR. ROSENBERG: Yes, I'm Amy
Rosenberg,
15 the
Director of the Division of Therapeutic
16
Proteins. And while I agree I
think it would be
17
difficult to characterize these receptors,
18
especially functionally, I don't think it's
19
impossible. Techniques of laser
capture and
20
micro-dissection and protein arrays that can assess
21 via
antibodies--antibody arrays, phosphorylated
22
proteins, are available. I think
rather than
190
1
conclude that it's impossible, perhaps it would be
2
instructive to find out whether using more novel,
3 new
techniques, it's possible to look at this.
4
Because, otherwise, we're not going to know
5
anything about the biology. We're
not going to
6
know--you get a clinical result; you're not going
7 to
know how to correlate that with functional
8
effects, especially for tumor activity.
9
So I think it's actually a critical point.
10 I
think we'll learn very little except a clinical
11
outcome if we don't try and pursue it.
And I think
12
there are ways to pursue it, and I think that those
13
should be looked into.
14
DR. CHESON: My concern is that
these are
15
multicenter and perhaps multinational studies
16
where--I guess our colleague who is the expert over
17
there might want to comment again about whether
18
there are enough reference laboratories that could
19 do
these or the samples could be shipped in, what
20 the
feasibility is for shipped samples versus
21
on-site samples, et cetera, et cetera.
22
DR. LODISH: Well, as I tried to indicate
191
1 in
my earlier presentation, we're at a level of
2
research rather than a robotized, commercialized
3
assay that could be done reproducibly.
I think
4
things like laser capture to isolate tumor cells,
5
arrays at an ultra-micro-level clearly are the wave
6 of
the future, but they're not practical now.
And
7
certainly in a clinical setting I couldn't advocate
8 for
them at all. And--well, let's end it
there.
9 Ten
years from now, we may revisit the system.
10
DR. CHESON: Thank you.
11
DR. DeLAP: A comment?
12
DR. CHESON: Okay.
13
DR. LEVINE: Mark Levine,
McMaster. The
14
proposed trial is in women with metastatic breast
15
cancer. It's very difficult to
get fresh tissue in
16
those patients. If there's chest
wall disease and
17 so
on, it's possible, but our experience, many of
18 us
in the room, of doing trials in metastatic
19
breast cancer, it's not like adjuvant.
It's not
20
early-stage breast cancer. So I
don't think it's
21
feasible.
22
DR. CHESON: I think the only
setting
192
1
where it may be possible is in a very limited
2
single institution or maybe a couple of
3
institutions who are part of the large cooperative
4
arrangement doing it on a very pilot, very
5
experimental basis as an exploratory issue. But to
6 do
it as part of this sort of trial, with these
7
sorts of trials, and which diseases would you do
8
them in, again, if you talk about micro arrays and
9
those things, they're going to differ from disease
10 to
disease, stage to stage. If you look at
11
lymphomas, even within histology of multiple
12
different array patterns, I'm not sure that we are
13
quite there yet.
14
Dr. Keegan, did you want to say something?
15
DR. KEEGAN: I think that the
sentiment
16
behind this question was really one of
17
generalizability. If we do a
study and we see a
18
negative outcome, an adverse outcome, do we
19
generalize it to all tumors?
Similarly, if we see
20 no
evidence of an effect, do we generalize it?
And
21
this was one attempt to try and look at possible
22
mechanisms by which this might be affecting it.
193
1
If there's agreement that it can't be done
2 in
the clinical trials due to lack of technology, I
3
think we have left open the possibility of trying
4 at
least to characterize different tumor types
5
through tissue banks or other means so that we can
6 put
the results of different trials in context,
7
particularly if we get answers that are not
8
consistent between different tumor types. I think
9
that was our concern also in terms of how one
10
chooses to select the tumor types to begin with.
11
DR. CHESON: I think this is an
excellent
12
target for FDA-directed funded research.
13
[Laughter.]
14
DR. CHESON: Dr. Brawley?
15
DR. BRAWLEY: You know, I was
wondering,
16 are
we going to start doing a number of biopsies on
17
perhaps thousands of patients that are unnecessary?
18 If
you have to go get the tissue, you know, for
19
clinical reasons, that's one thing.
But to just do
20 the
biopsy for the purposes of doing the biopsy for
21
science, that's another issue beyond the logistics
22 of
how the tissue is going to be handled, you know,
194
1
minus 70 or liquid nitrogen and so forth, and the
2
transport and logistical issues.
I think we have
3 to
worry about that ethical issue.
4
DR. CHESON: Well, a lot of those
5
questions, such as transport, et cetera, can be
6
done on non-human tumor samples.
7
DR. BRAWLEY: Right.
8
DR. CHESON: But, for example,
doing
9
biopsies, the CLGB is going to be conducting a
10
lymphoma trial looking at micro arrays and diffuse
11
large B-cell lymphoma prospectively, and it will
12
require needle biopsies of patients who have
13
already been biopsied. And we
expect it's going to
14
hamper accrual because a lot of people won't want
15 to
be re-biopsied, but to some the information will
16 be
of sufficient importance that it may be of
17
interest and whatever.
18
Dr. Feldman?
19
DR. FELDMAN: Yes, I'd like to
separate
20 out
the issue of feasibility with that of
21
relevance, and I agree that it probably is not a
22
very feasible thing to do, whether it's in a
195
1
clinical trial or samples shipped to research
2
laboratories.
3
But I would disagree with those who think
4
that this may not be relevant, and I think it would
5 be
very important, whether it be by FDA-directed
6
research or some other preclinical way, to find out
7 the
precise relevance of these EPO receptors on
8
tumors.
9
DR. CHESON: Absolutely. We're not
10
disagreeing with that.
11
DR. FELDMAN: Particularly in
those
12
tissues where normal tissue does not have EPO
13
receptor and tumor does, which includes the breast.
14
DR. CHESON: We agree that is a
scientific
15
question of importance. It's just
the feasibility
16 in
a large-scale trial that we were considering at
17 the
moment.
18
Dr. George?
19
DR. GEORGE: Just to follow up on
20
something Dr. Keegan said, just a warning. I
21
predict that you will get results that are going to
22 be
hard to interpret. They're not going to
be
196
1
entirely consistent. So it may be
how you think
2
about this ahead of time. It may
be a good time to
3 do
that, how you're going to put all this together.
4
DR. WEISS: We'll come back to you
at this
5
committee when those results are all there.
6
DR. CHESON: We will look forward
to it.
7
[Laughter.]
8
DR. KEEGAN: I think to go to your
point
9 and
to correct something that you said, Dr. Cheson,
10 in
fact, we have only begun to look at this
11
information, and we have not even reviewed the
12
protocols because most of these were actually not
13
company-sponsored trials. We
really haven't gotten
14 to
that yet. So we have not--I mean, this
is very
15
timely advice for us in looking and giving guidance
16 and
the necessity for getting additional
17
information. So we will look at
it with an eye to
18
getting inconsistent results across products,
19
across trials, and try and build into that, and we
20 may
need to come back to you on some of those
21
issues.
22
DR. CHESON: Now would be a good
time to
197
1 get
the protocols to ensure the consistency, so
2
that you get the answer, and you find out in five
3
years that someone didn't do what needed to be
4
done.
5
Who was over there? Dr. Bauer?
6
DR. BAUER: To reiterate a theme
here, you
7
know, that any results that are obtained in one
8
tumor type I think are -- [microphone off] -- it's
9 not
generic anemia. This is something that's
10
tumor-specific, potentially treatment-specific,
11
given the design of the trials, chemotherapy in
12
some and radiation in others--I'm sorry--will be
13
lack of generalizability from one tumor to another.
14
DR. CHESON: I think we have many,
many of
15 the
important tumor types included here, so we will
16 get
generalized information. So that's our
sense
17 on
this particular question. Do we need to
18
summarize it any more, or have we got it? Okay.
19
The next one, clinical conditions
20 comprising
thrombotic and cardiovascular events
21
vary from study to study. What
are those specific
22
events that are clinically important?
198
1
I think we kind of all agreed on most of
2
them--didn't we?--that were in the protocols.
3
There was one where Dr. Luksenburg excised chest
4
pain, and a number of us were discussing this, and
5 we
were wondering if you had actually gone into the
6 study
data to find out what that chest pain really
7 was
and whether it might not have been really
8
relevant to the trial, and not before these were
9
just tossed out.
10
DR. LUKSENBURG: I don't think we
have
11
that specificity of attribution, just as chest
12
pain.
13
DR. CHESON: Okay. So it's kind of hard
14 to
arbitrarily just yank them all.
15
Dr. Keegan, did you have something?
16
DR. KEEGAN: That's what I was
going to
17
say. That's actually the problem
with a lot of
18
safety data that we collect, that if you don't
19
target in advance what you want, you get things
20
that are coded in ways that make it difficult to
21
determine what it is you're looking at.
In the
22
particular study that Harvey was alluding to, that
199
1 was
actually in lung cancer. And so we
thought it
2
would be particularly difficult there to determine
3
what the chest pain was attributed to.
But what we
4
need are specific items to make sure that we're
5
capturing the relevant and important--
6
DR. CHESON: Now, in--I forget
which of
7 the
two partners here had a slide of eligibility
8 and
toxicity and listing what were considered
9
cardiovascular problems. If
someone would just put
10 it
up here real quick so we can say yea or nay and
11
come to agreement?
12
DR. DeLAP: I think we can do
that. I
13
think alternatively we could--we have Dr. Mark
14
Levine with us, and he could speak to what's
15
necessary or--well, okay. This is
a broad
16
definition. Obviously, there are
a lot of subcategories
17
that feed into these major categories.
18 But
there are venous and arterial, so there are
19
deep venous thrombosis, pulmonary embolism,
20
arterial thrombosis, myocardial infarction,
21
cerebral vascular accident.
22
I think what I'd come back to, though, is
200
1
what I think Dr. Keegan was saying, that if we're
2
going to study this, we need to study these as
3
endpoints rather than as serious AEs, such as kind
4 of
get collected in a study. So I was just
going
5 to
ask Dr. Levine if he had any comments about how
6 we
should do this as study endpoints.
7
DR. LEVINE: I'll just be
brief. I think
8 the
agency--and Ken Bauer well knows that in the
9
thrombosis trials that the agency looks at, there
10 are
standard definitions for objectively documented
11
pulmonary embolus, deep vein thrombosis; on the
12
arterial side, myocardial infarction and stroke.
13
They're well defined in the literature, and that's
14
what should be defined prospectively, and I think
15
that would advance the field much more than just
16
looking at AE forms.
17
DR. CHESON: Now, are you
suggesting that
18
there be some sort of ongoing screening for these
19
events or that there just be a heightened awareness
20 of
their clinical presence?
21
DR. DeLAP: I think that we're
agreeing
22
that this is an issue that needs further research,
201
1 and
I think that there needs to be structured
2
research in future protocols so that we're all
3
talking about the same thing and we're actually
4
assessing these in a precise way so that we can get
5
answers and actually start making comparisons
6
across trials and those kinds of things.
7
DR. CHESON: Dr. Bauer?
8
DR. BAUER: It's pretty
clear. We're
9
talking about symptomatic endpoints.
We're not
10
talking about routine screening.
So we're talking
11
about clinically symptomatic relevant events, which
12 are
different for other FDA-approved indications
13 for
prophylaxis. We're talking about
patients who
14
present--
15
DR. CHESON: So you will miss
things, but
16
they're probably not clinically relevant.
17
DR. BAUER: Well, the important
thing is
18
that the symptomatic events then be objectively
19
documented by appropriate radiographic studies, and
20
that's what sometimes is lacking in AEs, that
21
patients are--if they're suspected of having a
22
thrombotic event that they're objectively diagnosed
202
1 by
appropriate imaging studies, and that's what we
2
really need.
3
DR. CARPENTER: And the other
thing that
4
will turn out to be important is to ask--since
5
these are going to be symptomatic things, to ask at
6
prespecified intervals so that if there are
7
differences which might occur, they can be picked
8 up
regularly. We won't bias the
ascertainment.
9
DR. CHESON: And I think we need
to also
10
have careful histories for pre-existing conditions
11 and
that these things be evaluated such as
12
with--I'm surprised you didn't say that--looking
13 for
hypo-coagulable conditions, the factor
14
deficiencies and what have you, protein
15
deficiencies.
16
DR. KEEGAN: Are you suggesting
that as
17
eligibility criteria, Dr. Cheson?
18
DR. CHESON: No. I'm suggesting that you
19
take a careful history as part of the entrance onto
20 the
study, that we know whether there is a family
21
history or personal history of prior DVTs,
22
cardiovascular disease, et cetera.
203
1
DR. KEEGAN: Right. But in the absence of
2
specifically developed case report forms, I think
3 the
likelihood of getting good, quality data on
4
that might be difficult. I'm not
sure if the
5
ongoing--I mean, remember, we're playing catch-up
6
here--these ongoing trials are specifically
7
capturing that information.
8
DR. CHESON: Just a suggestion.
9
Dr. Reaman?
10
DR. REAMAN: I was going to
actually ask
11
how--I certainly applaud the use of these as study
12
endpoints instead of just AE findings.
But how is
13
that going to impact on the ongoing trials that are
14
actually going to be used to answer these
15
questions. Are there plans to
amend studies
16
looking at these at study endpoints?
17
DR. PARKINSON: Just a couple of
comments.
18
First is we've generally not used these as
19
endpoints but, rather, as prespecified points of
20
interest, and that's probably a good way to go, as
21 I
think you just suggested, Dr. Keegan.
22
With respect to the ongoing trials, we're
204
1
very much interested in the committee's
2
recommendations in this regard.
Clearly, they need
3 to
be followed--they need to be followed as
4
prespecified points of--pieces--what do you call
5
that? Events of interest. I was thinking of
6
points of light there for a second.
7
But one of the things, I think, that might
8 be
very interesting--and I'd ask the committee for
9
their advice--is about using common prespecified
10
events of interest to allow comparability in
11
different clinical trial settings, because clearly
12
this is complicated. We have
analyzed thrombotic
13
events every which way but loose since these trials
14
were--not published, but the results became
15
available. And so you find an
association which is
16
rather weak with the use of epoetins.
The highest
17
association is a history of prior thrombotic event.
18
Another association, which is independent,
19
relates to performance status.
We've never
20
excluded patients with prior thrombotic event from
21 our
trials. That may not always be the
case. So
22
there are a number of parameters and a number of
205
1
collection parameters that would be nice to be
2
standardized in the interest of trying to get
3
closer, as we all I think are interested in here
4
today, closer to the real answers.
5
DR. DeLAP: If I could just add,
we've
6
started to collect that kind of information in our
7
latest clinical trials, you know, more
8
prospectively, but obviously it will be very
9
helpful, as Dr. Parkinson says, if we have a
10
uniform way of doing it so that we can, you know,
11
compare notes, as it were, and get meaningful
12
interpretations in multiple trials.
13
DR. CHESON: Thank you.
14
Getting just to the last--yes?
15
DR. WEISS: Just a real quick
16
clarification. So you talked
about getting a good,
17
careful history, family history, prior histories,
18 et
cetera, maybe detecting undisclosed
19
hypo-coagulability states. Are
people thinking,
20
though, something that Dr. Parkinson alluded to,
21
that those people should be excluded from trials or
22
just carefully document it so you can try to
206
1
evaluate what their risks are relative to other
2
populations and trials?
3
DR. PARKINSON: You know, I think
we're
4 all
interested in real-world answers because these
5
drugs are really used, generally.
Because we have
6 not
excluded patients with prior thrombotic events,
7 our
rates actually reflect real-world use of the
8
drug in patients even with a prior history of
9
thrombotic event.
10
That would be our feeling, but we'd be
11
interested in the committee's discussion on this.
12
DR. CHESON: I'm all for the real
world.
13
[Laughter.]
14
DR. CHESON: I knew you'd like
that.
15
Have you all gotten from the committee
16
what you need on this particular question?
17
DR. KEEGAN: I think we've gone a
long
18
way. I just would ask if Dr.
Bauer would comment a
19
little bit on the type of documentation that you
20
would like for these sorts of events so that while
21
we're still in the public forum here you could
22
comment on how these should be documented for
207
1
purposes of data collection.
2
DR. BAUER: You know, for the five
3
entities that Mark Levine put up, there's strict
4
criteria, be it, you know, CT, angiography, or
5
ultrasound for a leg DVT and stroke and so forth,
6 and
myocardial infarction, standard criteria.
So I
7
think that suffices.
8
Let me just go back to this issue of
9
screening regarding eligibility.
I think it should
10 be
simple, and the strongest issue you'd want to
11
know about is really personal history of prior
12
thrombosis. And I guess at a
minimum for this kind
13 of
trial, I guess I would be uneasy about enrolling
14
people with prior history of thrombosis in this
15
trial as the only real exclusion, other than a
16
known thrombophilic disorder. I'm
not advocating
17 it
by any which way routine screening. But
the
18
issue, I think, of enrolling people who have had
19
documented prior thrombosis, you know, I think is
20 an
issue for the FDA and trial design, since I
21
gather they are allowing people to enroll who have
22 had
prior thrombosis.
208
1
DR. PARKINSON: We didn't actively seek to
2
enroll them. Let me make that
clear.
3
[Laughter.]
4
DR. PARKINSON: We did not exclude
them,
5 and
we recorded that information, which is why we
6 can
present to you do our analysis of this.
And
7
that is, I think, what we would advocate.
8
DR. CHESON: But the other issue
is that
9
patients with cancer are already at the increased
10
risk of thrombotic events.
11
DR. PARKINSON: TE-25--oh, sorry.
12
DR. CHESON: What?
13
DR. PARKINSON: That analysis is
actually
14
quite interesting. This is the
pooled oncology
15
trials analysis looking at this potential
16
interaction between this history of prior
17
thrombotic event and treatment.
It's interesting.
18
I'll leave it to you to interpret.
19
DR. DeLAP: Our data also says
that the
20
biggest predictor of whether a patient is going to
21
have a thrombotic episode on the trial is if they
22 had
one before, both in the placebo group and in
209
1 the
treatment group. And, in fact, the other
thing
2 I
would just add is that in looking at the
3
different subsets of numbers of risk factors for
4
thrombotic events, it looks like there is some
5
added risk with erythropoietic therapy at any given
6
baseline risk. But it's not
something that gets
7
profoundly worse at the higher baseline risk. So I
8
wouldn't--you know, I think it's better, as was
9
said before, to include as broad a population of
10
patients as you can and see what the answer is.
11 And
the data that we have suggests that you can
12
actually enroll patients with a fairly significant
13
underlying risk of thrombotic events, and you may
14 see
some additional risk, but it doesn't look like
15
it's a profound additional risk on top of the
16
underlying risk.
17
DR. CHESON: Dr. Bauer?
18
DR. BAUER: I dare say, with the
consent
19
form pretty prominently in, you know, risk of
20
thrombosis is one of the adverse effects, in the
21
real world you're going to get very few of these
22
people into these trials.
210
1
DR. CHESON: I think that gets to
the last
2
question, and that is, Should we have special
3
trials risk for high risk and low risk?
And I
4
think that would be a difficult set of trials to do
5
because they all become at high risk when they have
6
cancer; it's just that some are higher than others.
7
And I'll repeat my question of the agency.
8 Are
there any other issues that we have not
9
addressed to your satisfaction this morning?
10
DR. KEEGAN: I just want to make a
comment
11
about an issue that was raised that I don't think
12 was
fully resolved, and that was the concern about
13
looking at impact on overall survival because of
14 the
difficulties with interpretation of data
15
following completion of the treatment.
And I would
16
like to make it clear that our feeling is that
17 there
may be difficulties in interpretation, but we
18
don't think that that difficulty should preclude
19 our
attempts to determine if there are survival
20
impacts. So that while
progression-free survival
21 is
an important endpoint to look at, we should also
22
attempt to address the question on survival.
211
1
DR. CHESON: I agree. Whereas
2
progression-free survival to many of us is the
3
preferred primary endpoint in this setting, the
4
trials should be powered to adequately detect
5
survival differences as well as secondary
6
endpoints.
7
Are there any--overall survival,
8
right--additional comments from the committee? I
9 see
two hands up. Ladies first. Dr. Taylor?
10
DR. TAYLOR: Well, I would agree,
you have
11 to
look at overall survival, because I still go
12
back that we don't know what the mechanism is for
13
erythropoietin effect on survival.
And to just
14
look at progression-free survival is not going to
15
answer that question. And, yes,
there will be
16
difficulties, but we have to know what that is.
17
DR. CHESON: Dr. Grillo-Lopez?
18
DR. GRILLO-LOPEZ: I believe that
these
19
studies are a real challenge.
They are difficult
20
conduct and difficult to interpret at the end. And
21 one
additional factor that we haven't mentioned is
22 the
use of concomitant medications which might be
212
1
anti-coagulant or pro-coagulant in nature.
2
And, again, we haven't seen the protocols,
3 as
you have said, but I would assume that the
4
sponsors are collecting data on concomitant
5
medication because it's fairly standard.
However,
6
it's important also to understand that the severity
7 of
an adverse event is also going to be impacted by
8 how
rapidly therapy is instituted, what kind of
9
therapy, and then the duration of that event is
10
also impacted by those considerations.
11
So it's just additional data that needs to
12 be
collected in order to make sense of the results
13 at the end.
14
DR. CHESON: Very good point.
15
Any other comments or questions?
16
[No response.]
17
DR. CHESON: If not, I would like
to thank
18 the
sponsors for their excellent presentations,
19
carefully prepared, full of interesting data, and
20 to
my colleagues in the agency and on the panel for
21 a
very lively, interactive, and hopefully
22
productive discussion.
213
1
DR. WEISS: We second that. Thank you for
2 all
your input.
3
DR. CHESON: We'll be back here at
4
12--make it 1 o'clock. We'll give
an extra five
5
minutes. Thank you.
6
[Luncheon recess.]
214
1
A F T E R N O O N P R O C E E D I
N G S
2
[1:00 p.m.]
3
DR. KELSEN: Good afternoon. My name is
4
David Kelsen, and I'm a former member of ODAC, and
5
I've been asked to serve as Acting Chairman this
6
afternoon. And I'd like to
welcome you this
7
afternoon to a session which will discuss endpoints
8 for
colorectal cancer, regulatory approval.
9
Before we begin the session, I'd like to
10 ask
the members of the committee to introduce
11
themselves, and we'll start with Dr. Grillo-Lopez.
12
DR. GRILLO-LOPEZ: I'm Antonio
13
Grillo-Lopez. I am a
hematologist/oncologist with
14 the
Neoplastic and Autoimmune Diseases Research
15
Institute.
16
MS. ROACH Nancy Roach from the
Marti
17
Nelson Cancer Foundation, and I'm the patient rep
18 for
this session.
19
DR. SARGENT: Dan Sargent,
biostatistician
20
from the Mayo Clinic.
21
DR. O'CONNELL: Michael O'Connell,
medical
22
oncologist and Director of Allegheny Cancer Center
215
1 and
Associate Chair of the NSABP.
2
DR. BRAWLEY: Otis Brawley. I'm a medical
3
oncologist and epidemiologist from Emory
4
University.
5
DR. MARTINO: Silvana Martino,
medical
6
oncology, from the John Wayne Cancer Institute.
7
DR. TAYLOR: Sarah Taylor, medical
8
oncology, palliative care, University of Kansas.
9
DR. REAMAN: Gregory Reaman,
pediatric
10
oncologist, the George Washington University and
11
Children's National Medical Center.
12
DR. REDMAN: Bruce Redman, medical
13
oncologist, University of Michigan.
14
MS. CLIFFORD: Johanna Clifford,
FDA,
15
Executive Secretary to this meeting.
16
DR. CHESON: Bruce Cheson, Georgetown
17
University, Lombardi Comprehensive Cancer Center.
18
DR. GEORGE: Stephen George,
Biostatistics, Duke
19
University.
20
MS. HAYLOCK: Pamela Haylock,
oncology
21
nurse, and I'm the consumer representative.
22
DR. CARPENTER: John Carpenter,
medical
216
1
oncologist, University of Alabama at Birmingham.
2
DR. RODRIGUEZ: Maria Rodriguez,
medical
3
oncologist, M.D. Anderson Cancer Center in Houston.
4
DR. DuBROW: Ronnie DuBrow. I'm a
5
radiologist at M.D. Anderson Cancer Center in
6
Houston also.
7
DR. IBRAHIM: Amna Ibrahim, medical
8
officer, Division of Oncology Drug Products.
9
DR. HIRSCHFELD: Steven
Hirschfeld,
10
pediatric oncologist, Center for Biologics, FDA.
11
DR. WILLIAMS: Grant Williams,
Deputy
12
Director, Division of Oncology Drug Products.
13
DR. KEEGAN: Patricia Keegan,
Division
14
Director, Oncology Biologic Products.
15
DR. PAZDUR: Richard Pazdur,
Division
16
Director, Oncology Drug Products, FDA.
17
DR. KELSEN: Thank you. I'll ask Ms.
18
Clifford to read a statement about conflict of
19
interest.
20
MS. CLIFFORD: Thank you. The following
21
announcement addresses conflict of interest issues
22
with respect to this meeting and is made a part of
217
1 the
record to preclude even the appearance of
2
impropriety at this meeting.
3
The topics to be discussed this afternoon
4
will not focus on any particular product or company
5
but, rather, may affect all manufacturers of
6
products to treat colorectal cancer.
The conflict
7 of
interest statutes prohibit special government
8
employees from participating in matters that could
9
affect their own or their employer's financial
10
interests. All participants have
been screened for
11
interests in the products and companies that could
12 be
affected by today's discussions.
13
In accordance with 18 U.S.C, Section
14
208(b)(3), the Food and Drug Administration has
15
granted waivers to Dr. David Kelsen and Dr. Daniel
16
Sargent because it has determined that the need for
17
their services outweighs the potential for a
18
conflict of interest. A copy of
the waiver
19
statements may be obtained by submitting a written
20
request to the agency's Freedom of Information
21
Office, Room 12A-30 of the Parklawn Building.
22
We would also like to note that Dr.
218
1
Antonio Grillo-Lopez, Chairman, Neoplastic and
2
Autoimmune Diseases Research Institute, is
3
participating in this meeting as an industry
4
representative, acting on behalf of regulated
5
industry.
6
In the event the discussions involve
7
products or firms not on the agenda for which an
8 FDA
participant has a financial interest, the
9
participants are aware of the need to exclude
10
themselves from such involvement, and their
11
exclusion will be noted for the record.
12
With respect to all other participants, we
13 ask
in the interest of fairness that they address
14 any
current or previous financial involvement with
15 any
firm whose product they may wish to comment
16
upon.
17
Thank you.
18
DR. KELSEN: Thank you. We'll open this
19
afternoon's session with opening remarks from Dr.
20
Pazdur.
21
DR. PAZDUR: I have to take a look
at the
22
audience, and I noticed that it's really dropped
219
1
down in attendance, and perhaps it reflects the
2
departure of the stock analysts since we're not
3
talking about any product-specific application
4
here.
5
I began the comments on Monday, and the
6
presentation that I'm going to give I think is very
7
similar to what I gave in my introductory remarks
8
before we discussed the two drugs on Monday. And I
9
just want to go over some of these points because I
10
think that these points are germane not only to the
11
discussions that we had on Monday, but also are
12
germane to a discussion on colorectal cancer
13
endpoints, and these are recurring themes over and
14
over and over again.
15
The agency is open. That's why
we're
16
having this discussion with you.
We want
17
transparency of process. We want
to make sure that
18 the
endpoints that we select and discuss with our
19
regulated industry are ones that really measure the
20
true efficacy of the drug, are really going to give
21 us
a determination of why we should approve a drug.
22
As you are all aware of, we have
220
1
traditionally held to the standard of the
2
demonstration of a survival advantage for the
3
approval, the regular approval of a drug in the
4
first-line setting, and also in the adjuvant
5
setting of colorectal carcinoma.
And as I
6
mentioned and we discussed throughout these
7
proceedings, we've looked at survival as an
8
unambiguous endpoint. It's
measured on a daily
9
basis. We feel that given an
accepted safety
10
profile that it is the ultimate in clinical
11
benefit.
12
But, nevertheless, as I stated in my
13
opening comments on Monday, we realized that there
14 can
be shortcomings of a survival analysis,
15
depending on what setting one is looking at.
16
Obviously, survival analysis requires large numbers
17 of
patients. This may or may not be a
problem in
18
colorectal carcinoma. Obviously,
it's not as big a
19
problem in colorectal carcinoma as it would be, for
20
example, in hairy cell leukemia or in lymphoma.
21
There are problems perhaps with long
22
patient follow-ups, which generally is not that big
221
1 of
a problem in metastatic colorectal carcinoma,
2 but
with improvements in survival, fortunately, we
3 are
seeing that patients with colorectal carcinoma
4
live longer.
5
Perhaps one of the areas that we're most
6
concerned about is this issue of crossover, and
7
crossover can go two ways, and we've seen this in
8
discussions of applications.
Obviously, it can
9
obscure a survival advantage in a randomized study,
10 but
if there is an unequal crossover going in one
11
direction, it may actually provide you the
12
suggestion, at least of an erroneous conclusion
13
based on survival.
14
So, by all means, all of our endpoints
15
that we have are far from perfect, and I think
16
people have addressed this throughout the day.
17
We're here to get your consensus and your feeling
18 on
where we should go with our discussion with
19
industry in the future.
20
I think when we talk about the specifics
21
here, let's go over endpoints, and I think issues
22
that we need to focus on--and we will be focusing
222
1 on
these during the presentations, but also in the
2
discussion. When we take a look
at the adjuvant
3
setting and look at disease-free survival, I think
4 we
have important questions that we must address.
5 If
we accept this as a regulatory endpoint, are we
6
saying that disease-free survival is a surrogate
7 for
survival, overall survival? Is it
reasonably a
8
likely surrogate for overall survival?
And those
9 are
the key words for accelerated approval.
Is it
10 a
surrogate for an improved life because one delays
11 the
uncertainties of the diagnosis of cancer being
12
made in an adjuvant setting at the time of relapse?
13 So
there are issues here that I think we need to
14
address when we talk about disease-free survival.
15
When we talk about in the advanced disease
16
setting, when we're talking about time to
17
progression or progression-free survival, again,
18 are
we saying it is a surrogate for survival or is
19 it
a really true endpoint of clinical
20
meaningfulness in itself? And
those are some of
21 the
questions that we will be posing to you.
22
In the two applications that we saw
223
1
yesterday, especially with the first, I think there
2
were important questions that we discussed
3
regarding the rigor of measurement of a time to
4
event endpoint such as progression-free survival.
5 One
has to account for missing visits, asymmetry of
6
follow-ups. What is the role of
an external
7
radiology committee vis-a-vis the response or the
8
progression determination, I should say, of the
9
actual investigators that are seeing these
10
patients? And could this vary
from disease to
11
disease? For example, in colon
cancer where most
12 of
the progression is picked up on CT scan, are
13
investigators' determinations in a randomized study
14
which might balance out clinical findings of
15
progression really going to be that important when
16 we
have a discussion of what is the role of a
17
radiology committee?
18
We've had a tendency for recent
19
applications--and you've seen these because they've
20
come to you--to be asked to make decisions on the
21
basis of one trial. Should we
require a greater
22
degree of statistical significance if we take a
224
1 look at one trial versus two trials? I'll let you
2
know as a caveat that there are many divisions in
3 the
FDA that do look at a higher degree of
4
statistical persuasiveness when they examine one
5
trial. If we move away from survival,
would this
6 be
especially important to require a higher degree
7 of
statistical significance?
8
As we had in our discussion of the morning
9
application on Monday, what is the value of a small
10
increment in progression? How
does one define that
11 as
one enters the trial prospectively with the
12
company?
13
So these are just some of the questions
14
that I want to pose to you. Here,
again, our whole
15
purpose in looking at this is a degree of
16
transparency. We're open. We want to make sure
17
that we're giving the correct advice to patients.
18 I
always say there are sins of omission and sins of
19
commission when we're in drug development and
20
making regulatory decisions. Many
times the
21
marketplace itself will address a bad drug that's
22 out
there. People simply won't use it. However,
225
1 if
drugs don't get out there, the marketplace and
2
market forces cannot answer that question. And,
3
obviously, there is always a degree of balance.
4
What we're looking for, however, when we have an
5
ODAC meeting such as this is what is the rigor,
6
what is the science that would go into making these
7
decisions.
8
Thank you very much.
9
DR. KELSEN: Thank you, Dr.
Pazdur.
10
I'll ask Dr. Ibrahim now to discuss
11
regulatory background and past approvals.
12
DR. IBRAHIM: Good afternoon. I will be
13
discussing the regulatory background and past FDA
14
approvals in colorectal cancer.
15
First, the presentation outline will be as
16
follows: I will discuss a
background of regulatory
17
requirements for drug approval, endpoints for
18
regular and accelerated approval, agents approved
19 for
adjuvant, first-line, and recurrent therapy of
20
colorectal cancer, and endpoints used for them will
21 be
presented. I will review briefly the
major
22
trials that led to drug approval, first for drugs
226
1 for
adjuvant therapy and then for first-line and
2
second-line therapy. Finally, I
will conclude with
3 the
endpoints that have supported approval of drugs
4 for
colorectal cancer in these three treatment
5
settings.
6
Drug approval requires adequate and
7
well-controlled studies demonstrating that the drug
8 is
safe and is effective for the approved
9
indication. The safety
requirement comes from the
10
Federal Food, Drug, and Cosmetic Act of 1938. The
11
efficacy requirement is from a 1962 amendment to
12 the
Act.
13 There are two routes to a new drug
14
approval. The traditional route
is a regular
15
approval. Sometimes it is
referred to as full
16
approval. It requires the
demonstration of
17
clinical benefit or an effect on an established
18
surrogate for clinical benefit.
Clinical benefit
19 is
usually considered to be tangible benefit of
20
obvious worth to the patient, such as prolongation
21 of
survival or relief of pain.
22
Sometimes FDA has accepted surrogates as
227
1 the
basis for regular approval, usually after much
2
clinical experience with the surrogate and
3
widespread acceptance by patients and physicians.
4 Examples
are lowering blood pressure and lowering
5
cholesterol. On occasion, these
assumptions of
6
obvious benefit have been proven wrong, such as the
7
benefit of suppressing some arrhythmias.
8
Another mode of approval is accelerated
9
approval, approval which can be based on a
10
surrogate endpoint considered to be reasonably
11
likely to predict clinical benefit.
I will discuss
12
accelerated approval in a later slide.
13
One of the central questions we address at
14 the
end of Phase II meetings is: How many
trials
15 are
needed for approval? The usual answer is
more
16
than one, and this is based on the definition of
17
substantial evidence of effectiveness in the
18 amended
Food, Drug, and Cosmetic Act and the fact
19
that the word "trials" is plural in that
20
definition. Reasons for needing
additional
21
evidence are the possibility of unrecognized trial
22
bias and also just chance alone.
228
1
However, FDA has recognized that sometimes
2
results from a single trial may suffice.
Although
3
approvals based on a single trial have been granted
4 on
occasion for many years, this practice was
5
written into law by the FDA Modernization Act, or
6
FDAMA, in 1997. The possible use
of only one trial
7 was
also detailed in the FDA Effectiveness
8
Guidance, finalized in 1998. As
worded in that
9
guidance, a single trial may suffice, but generally
10
only in cases in which a single multicenter study
11 of
excellent design provided highly reliable and
12
statistically strong evidence of an important
13
clinical benefit, such as an effect on survival and
14 a
confirmatory study would have been difficult to
15
conduct on ethical grounds.
16
Regular approval requires evidence of
17
clinical benefit or improvement in an established
18
surrogate of benefit. In
oncology, survival is
19
obviously the gold standard for clinical benefit.
20 But
the FDA has accepted other endpoints for cancer
21
drug approval.
22
In the 1970s, FDA usually approved cancer
229
1
drugs based on objective response rates.
In the
2
early 1980s, after discussion with ODAC, FDA
3
determined that response rate was generally not
4
sufficient evidence for approval.
Given the
5 toxicity of cancer drugs, approval needed
evidence
6 of
improvement in survival or in a patient's
7
quality of life. Example: improved physical
8
functioning or improved tumor-related symptoms.
9
There have been recent examples of
10
endpoints that were accepted as established
11
surrogates of clinical benefit in specific cancer
12
settings. These endpoints
supported regular
13
approval. Disease-free survival
has been accepted
14 as
an adequate endpoint in the setting of adjuvant
15
treatment of breast cancer based on the belief that
16 a
large proportion of the recurrence were
17
symptomatic.
18
Durable complete response was considered
19 an
acceptable endpoint in testicular cancer and
20
acute leukemia because the untreated conditions
21
were quickly lethal, or even in some chronic
22
leukemias and lymphomas when it was clear that
230
1 remission
would lead to less infection, bleeding,
2 and
blood product support.
3
Even with solid tumors, the FDA has
4
suggested that tumor response may sometimes support
5
approval, but that this judgment needs also to
6 consider
additional evidence such as response
7
duration, relief of tumor-related symptoms, and
8
drug toxicity.
9
As discussed in the following sections,
10
response rate with adequate response duration has
11
sometimes supported either regular approval or
12
accelerated approval, especially in patients with
13
heavily pre-treated or refractory disease, and
14
especially with less toxic therapies, such as
15
hormone treatment of breast cancer.
16
Recently, the Division of
Oncology Drug
17
Products evaluated the basis of approvals since
18
1990 for drugs in our division.
As shown on this
19
slide, survival was the approval endpoint in the
20
minority of approvals: 73 percent
of all approvals
21
were not based on survival, and if you exclude
22
accelerated approvals, 67 percent of approvals were
231
1 not
based on survival.
2
Let's turn to accelerated approval.
This
3
slide lists the major issues. The
accelerated
4
approval regulations are for diseases that are
5
serious or life-threatening, where the new drug
6
appears to provide benefit over available therapy.
7 The
key point for our consideration is that
8
accelerated approval can be granted on the basis of
9 a
surrogate endpoint that is reasonably like to
10
predict clinical benefit.
11
After accelerated approval, the applicant
12 is
required to perform a post-marketing study to
13
demonstrate that the treatment with the drug is
14
indeed associated with clinical benefit.
If the
15
post-marketing study fails to demonstrate clinical
16
benefit or if the applicant does not show due
17
diligence in conducting the required study, the
18
regulations describe a process for rapidly removing
19 the
drug from the market.
20
The approved agents in the table are
21
listed according to the treatment setting with the
22
drugs for adjuvant use in the left column, for
232
1
first-line use in the middle column, and those for
2 the
recurring cancer in the column on the right.
I
3
will present them to you in chronological order.
4
5FU was the first drug approved for colon
5
cancer in 1962. We will not
discuss this further
6
since 5FU approval predated the era of controlled
7
clinical trials in oncology.
8
After a long gap, levamisole was approved
9 in
combination with 5FU in 1990 for adjuvant use.
10
Although reports in the literature have been
11
described regarding results supporting the use of
12 5FU
Leucovorin for adjuvant therapy, the FDA has
13 not
received an NDA submission supporting this
14
indication. Leucovorin was
approved in 1991 in
15
combination with 5FU for first-line therapy.
16
Irinotecan initially received accelerated
17
approval for recurrent colorectal cancer in 1996,
18
followed by a regular approval for the same
19
indication. Subsequently, in 2000
it was approved
20 for
first-line use.
21
Capecitabine is the only agent approved
22 for
first-line setting based on non-inferiority
233
1
analysis.
2
Oxaliplatin in combination with
3
5FU/leucovorin received an accelerated approval for
4 recurrent
colorectal cancer, which was converted to
5 a
regular approval, and then it was also approved
6 for
first-line therapy earlier this year.
7
Bevacizumab and cetuximab in 2004 are the
8
first biologic agents to have received approvals
9 for
first-line and recurrent colorectal cancer,
10
respectively. The approval for
bevacizumab was
11
regular, and for cetuximab it was accelerated.
12
As you will see, survival was the endpoint
13
supporting all regular approvals.
Randomized
14
trials demonstrating superiority led to all but one
15 of
the regular approvals. For one drug,
16
capecitabine, non-inferiority in overall survival
17
supported regular approval. Three
drugs received
18
accelerated approval in previously treated
19
populations. Two were supported
by a response rate
20 in
single-arm trials and one by a response rate and
21
time to tumor progression superiority shown in
22
interim analysis of a randomized trial.
234
1
Now, agents for adjuvant therapy.
2
Levamisole was approved in combination
3
with 5FU in 1990 based on the results of two
4
trials. After surgery, patients
were randomized to
5 no
further therapy, levamisole alone, or 5FU plus
6
levamisole. Levamisole plus 5FU
demonstrated a
7
reduction in death rate by about 30 percent. The
8
follow-up period was two to five years for these
9
studies. Although the
contribution of levamisole
10 to
this regimen was not demonstrated in clinical
11
trials, this was the first adjuvant regimen to show
12 a
survival benefit. And levamisole was
approved
13
based on these results.
14
Agents for first-line therapy.
15
The combination of 5FU/leucovorin was
16
approved for treatment of advanced disease in 1991.
17
Study 1 is a five-arm study, but for simplicity
18
only three arms are shown in this table.
A
19
randomized study demonstrated improvement in
20
response rate, time to tumor progression, and
21
overall survival of high- or low-dose leucovorin
22
combined with 5FU. These two arms
of the study
235
1
were extended along with sequential methotrexate,
2
5FU/leucovorin arm from the same study.
This is
3 the
study seen in the table. The results
remain
4
consistent with the initial study.
Overall
5
survival was about 12.5 months in the initial as
6
well as the extension of the study.
7
In 2000, irinotecan was approved for
8
first-line therapy following its initial
9
accelerated approval for refractory colon cancer.
10 Two
randomized, multicenter trials compared
11
infusion of 5FU/leucovorin plus or minus irinotecan
12 in
untreated patients. Each trial had over
300
13
patients and demonstrated an improvement in
14
response rate, time to tumor progression, and
15
overall survival.
16
These differences in survival were
17
observed in spite of second-line therapy in a large
18
number of patients on both arms, including
19
crossover to irinotecan-containing regimens in the
20
control arm.
21
Capecitabine is the only colon cancer drug
22
approved based on non-inferiority analysis. The
236
1
combined survival data from two open-label,
2
randomized trials of capecitabine versus
3
5FU/leucovorin formed the basis of approval.
4
Sufficient historical data existed to allow a
5
reasonably precise estimate of the effect of
6
5FU/leucovorin on survival. The
non-inferiority
7
analysis showed that at least 50 percent of the
8
5FU/leucovorin effect was retained by capecitabine.
9
This drug was approved for a restricted first-line
10
indication, "for patients when treatment with
11
thoropyrimidine(?) therapy alone is preferred."
12
One drug, oxaliplatin, and one biologic
13
agent, bevacizumab, were approved for first-line
14 use
in colon cancer in 2004. In one
randomized
15
trial, a combination of oxaliplatin with
16
5FU/leucovorin, known as the FOLFOX4 regimen,
17
demonstrated superiority in overall survival when
18
compared with the control regimen of IFL. The
19
study design was complicated, and there was an
20
unequal crossover. Twenty-four
percent of the
21
patients in the IFL arm received oxaliplatin in
22
their second-line therapy; whereas, only 8 percent
237
1 of
patients in the oxaliplatin combination arm
2
received irinotecan. An improved
time to tumor
3
progression supported the improved survival
4
observed in the FOLFOX4 arm.
Additionally, it
5
could be inferred that oxaliplatin plus
6
5FU/leucovorin administered sequentially with IFL
7 is
better than irinotecan plus 5FU/leucovorin
8
without oxaliplatin.
9
The safety and efficacy of bevacizumab in
10 the
initial treatment of patients with metastatic
11
carcinoma of the colon and rectum were studied in
12 two
randomized, controlled clinical trials in
13
combination with intravenous 5FU-based
14
chemotherapy. The results of the
larger trial with
15
over 800 patients demonstrated a superiority in
16
overall survival by about five months.
In the
17
smaller trial, a randomized, exploratory Phase II
18
trial with just over 100 patients, statistical
19
significance was observed only for progression-free
20
survival in the 5FU/leucovorin plus 5 milligrams of
21
bevacizumab. There was a trend
for improved
22
survival.
238
1
Agents for refractory cancer.
2
In 1996, irinotecan was the first
3
chemotherapy agent since 5FU to receive approval
4 for
treatment of pretreated, advanced colorectal
5
cancer. Three single-arm studies
with response
6
rate ranging from 14 to 21 percent and response
7
duration of 5.8 months led to accelerated approval
8 for
second-line therapy. A survival benefits
was
9
subsequently demonstrated in two randomized trials
10
shown in the next slide.
11
These randomized trials demonstrated
12
superiority in survival by 2 to 2.5 months against
13
best supportive care, and 5FU-based regimens led to
14
regular approval in the second-line setting.
15
Interestingly, these trials were not part of the
16
original regulatory plan to convert the accelerated
17
approval to regular approval.
While the single-arm
18
trials were being reviewed by FDA, these
19
confirmatory trials were being conduct in Europe.
20 The
initial agreement between the sponsor and FDA
21 was
that the trials in the first-line setting were
22 to
provide initial proof of clinical benefit.
239
1
Oxaliplatin in combination with
2
5FU/leucovorin received accelerated approval based
3 on
improved response rate and time to tumor
4
progression, shown at an interim analysis of a
5
three-arm randomized trials.
Patients in this
6
trial had disease which progressed on or recurred
7
within six months of treatment with the IFL
8 regimen. The oxaliplatin combination arm had a
9
response rate of 9 percent versus 0 to 1 percent in
10 the
single agent oxaliplatin arm and 5FU/leucovorin
11
control. The time to tumor
progression was
12
increased by two to three months compared to the
13
other two arms.
14
There were some important observations.
15
Because of the inclusion of the single agent
16
oxaliplatin arm, the contribution of 5FU/leucovorin
17 to
the combination regimen was shown definitively.
18 It
also demonstrated that oxaliplatin should not be
19
used alone in the pretreated population.
Follow-up
20 of
this study did not demonstrate a survival
21
advantage for the oxaliplatin regimen.
22
Cetuximab used in combination with
240
1
irinotecan received accelerated approval in 2004
2 for
the treatment of EGFR-expressing metastatic
3
colorectal carcinoma in patients who are refractory
4 to
irinotecan-based chemotherapy. An
accelerated
5
approval was also granted for cetuximab as a single
6
agent for the treatment of EGFR-expressing
7
metastatic colorectal carcinoma in patients who are
8
intolerant to irinotecan-based chemotherapy.
9
This regular approval is based on one
10
two-armed randomized trial and two single-arm
11
studies. The multicenter,
randomized, controlled
12
clinical trial was conducted in over 300 patients
13 randomized
to receive either cetuximab plus
14
irinotecan or cetuximab monotherapy.
Cetuximab
15
plus irinotecan improved time to tumor progression
16 by
about 2.5 months compared to the single agent
17
cetuximab.
18
In the single-arm trials, the overall
19
response rate was 9 to 15 percent for single agent
20
cetuximab and in combination with irinotecan. The
21
median durations of response were approximately 6.5
22 to
4.2, respectively.
241
1
In summary, the FDA requirements for drug
2
approval were reviewed, including the need for
3
evidence from well-conducted, well-controlled
4
clinical trials, or sometimes from a single trial
5
plus confirmatory evidence; and regular approval
6
which needs evidence showing clinical benefit or an
7
accepted surrogate for clinical benefit; and
8
accelerated approval which must show an advantage
9
with respect to available therapy and may use an
10
endpoint that is only reasonably likely to predict
11
benefit. We reviewed the approval
endpoints that
12 FDA
has accepted over the past several years.
13
I will conclude my presentation with this
14
slide, which gives an overview of the basis of
15
approval in colorectal cancer.
Levamisole with 5FU
16 is
the only drug approved for adjuvant therapy
17
after demonstration of superiority in survival.
18
Five drugs are approved for first-line therapy, and
19
they are 5FU, irinotecan, oxaliplatin, bevacizumab,
20 and
capecitabine. Superiority analysis for
first
21
(?) and non-inferiority for
capecitabine for
22
survival led to the approval.
Irinotecan,
242
1
oxaliplatin, and cetuximab are the three drugs that
2
have received accelerated approval for recurrent
3
disease based on response rate and on time to tumor
4
progression.
5
For irinotecan, clinical benefit, that is,
6
survival, was demonstrated later in two randomized
7
studies, leading to full approval in the recurrent
8
disease setting. Oxaliplatin's
accelerated
9
approval was converted to a regular approval on the
10
basis of a large randomized trial in previously
11
untreated patients.
12
Thank you.
13
DR. KELSEN: Thank you. We're going to
14
hold questions until after the two additional
15
presentations, and I'll now ask Dr. O'Connell if
16
he'll give his synopsis on the FDA Endpoints
17
Workshop.
18
DR. O'CONNELL: Thanks very much,
David.
19
My task today is to review for you the
20
results of the workshop sponsored by the FDA and
21
held on November 12th of last year.
I had the
22
privilege of co-chairing this meeting along with
243
1 Dr.
Pazdur. Dr. Williams and Dr. Ibrahim
also gave
2
presentations. Dr. Kelsen was a
panelist. Dr.
3
Sargent also gave a presentation there.
4
The purpose of that workshop was to
5
discuss both the positive and the negative aspects
6 of
various endpoints for approval of new drugs for
7
colorectal cancer. Specifically,
it was not reach
8 a
consensus or to give FDA any advice.
That's the
9 job
of this committee today.
10
Secondly, we were to identify areas for
11
further research that might help identify more
12
effective endpoints for colorectal cancer drug
13
approval.
14
And then third was to provide information
15 to
you so that you could give whatever
16
recommendations you think appropriate to the FDA
17
based upon this discussion.
18
The workshop consisted of a series of
19
presentations, very similar to the one you just
20
heard, regarding the regulatory background and the
21
summary of previous approvals.
There were five
22
presentations given by different panelists at this
244
1
meeting, and I'll briefly summarize these
2
presentations for you.
3
I said there was a very lively,
4
interactive discussion between the speakers and the
5
multidisciplinary panel. There
certainly was a
6
free range of expression of opinions on the various
7
endpoints. And then we concluded
with some
8
discussion of questions that were posed by the FDA.
9
My goal in this presentation today is to
10
give you a very brief capsule summary of the
11
presentations and the main points of discussion
12
without going through a litany of all of the
13
discussions that occurred over that six-hour
14
period.
15
The focus is really to provide some
16
information regarding new endpoints for regulatory
17
approval of drugs for colorectal cancer and, in
18
particular, there are three endpoints that are of
19
particular interest that I'll emphasize during my
20
presentation: time to progression
as a regulatory
21
endpoint for first-line metastatic colorectal
22
cancer; three-year disease-free survival as an
245
1
endpoint for regulatory approval in the colon
2
adjuvant situation; and three-year local control as
3 an
endpoint in rectal cancer adjuvant studies.
4
So let's briefly go through
the
5
presentations. One of these
presentations was
6
given by Dr. Charles Blanke from the University of
7
Oregon. His topic was the use of
biomarkers or
8
quality of life as regulatory endpoints for
9
patients with colorectal cancer.
There was a fair
10
amount of discussion regarding the use of the
11
carcino-embryonic antigen, or CEA, and it was the
12
point of view of the speaker and the panel that it
13
really wasn't possible to consistently predict
14
clinical benefit based on fluctuations of CEA.
15
Further, the ASCO guidelines do not
16
recommend other biomarkers for colorectal cancer,
17
including the variety of molecular markers that
18
have more recently been described in the
19
literature.
20
Dr. Blanke then went on to discuss the
21
pros and cons of quality-of-life analysis in
22
colorectal cancer patients. Of
course, he pointed
246
1 out
that there are multiple methodologic issues
2
involved with quality-of-life measurements,
3
problems with missing data, problems with perhaps
4 not
asking the correct question in the
5
quality-of-life questionnaire or instrument that's
6
pertinent to the particular disease process under
7
question.
8
He pointed out that it really isn't know
9
whether there are significant changes in
10
quality-of-life parameters in regimens known to be
11
effective in colorectal cancer and also pointed out
12 you
really can't discriminate between safety and
13
efficacy based on quality-of-life endpoints.
14
Perhaps one of the most important issues
15 was
that many patients with metastatic colorectal
16
really don't have significant tumor-related
17
symptoms. They don't have severe
pain. They don't
18
have a significant decrease in performance status.
19
Many of these patients are asymptomatic or have
20
minimal symptoms, questioning the use of resources
21 in
measuring this parameter in a population that
22
frequently does not demonstrate significant
247
1
symptoms.
2
Dr. Blanke then went on to discuss the
3
clinical benefit response, which, of course, was
4
used as a regulatory endpoint for approval of drugs
5 in
pancreatic cancer where most patients with
6
pancreatic cancer do have pain, do have significant
7
reduction in their performance status, and
8
frequently have significant weight loss.
Again,
9 the
issue with metastatic colorectal cancer, these
10
parameters are frequently not present.
11
Further, those three specific symptoms do
12 not
really adequately encompass the variety of
13
symptoms that patients with metastatic colorectal
14
cancer might experience related to bowel
15
obstruction, the development of ascites, liver
16
dysfunction and so on.
17
And, again, this type of clinical benefit
18
response was felt perhaps to be of most benefit in
19
patients that were likely to be very symptomatic,
20
which would include patients with rectal cancer to
21 a
much greater degree since patients with rectal
22
cancer frequently experience local tumor recurrence
248
1
which can result in severe pain, ureteral
2
obstruction, and other clinical problems.
3
Dr. Meg Mooney from the National Cancer
4
Institute then provided a discussion of endpoints
5 for
neoadjuvant and adjuvant therapy of rectal
6
cancer. Here, in
contradistinction to colon
7
cancer, the failures are frequently very
8
symptomatic, and there's a higher proportion of
9
locoregional failures as a component of the
10
failures in patients undergoing potentially
11
curative surgery. In fact, one of
the panel
12
members was very precise in stating that local
13
tumor control at three years is an appropriate
14
endpoint for full approval, and there were several
15
other members of the panel that had the same point
16 of
view and no dissent.
17
Pathologic complete response engendered
18
more discussion. If you have a
patient receiving
19
preoperative radiation and chemotherapy, one
20
measure of efficacy is to determine whether in the
21
resected specimen there's any histologic evidence
22 of
residual tumor. And although it was felt
to
249
1
definitely relate to biological activity, there
2
were quality control issues raised:
evaluation of
3 the
radium margin(?), quality control issues in
4
determining whether or not there truly was
5
microscopic residual disease. So
the general
6
feeling there was that pathologic complete response
7
might be premature as a regulatory endpoint at this
8
point.
9
Colostomy-free survival is the endpoint in
10 the
management of anal carcinoma, the clinically
11
relevant endpoint, and, in fact, would also apply
12 to
a certain subset of patients with rectal cancer,
13 but
only to patients that have very low-lying
14
tumors. And so for patients with
colon cancer or
15 for
rectal cancer above the very distal several
16
centimeters, this was not felt to be a helpful
17 endpoint
in colorectal cancer.
18
Dr. Tom Fleming from the University of
19
Washington then gave a very articulate and, in
20
fact, I would say, impassioned presentation
21
regarding surrogate endpoints and non-inferiority
22 trials. He pointed out, as you've already heard,
250
1
that primary endpoints for drug regulation need to
2 be
sensitive, measurable, and clinically relevant,
3
with the accepted endpoints or measures of clinical
4
benefit being improvement in survival or decrease
5 in
tumor-related symptoms.
6
He then went on to discuss surrogate
7
endpoints, pointed out that biological activity
8
might be reflected in a surrogate endpoint, but
9
that might not establish clinical benefit for
10
patients. He gave a couple of
examples from the
11
cardiovascular literature where flecainide and
12
other agents were used as antiarrhythmics and can
13
prevent ventricular tachycardia.
The surrogate
14
endpoint was improved but, unfortunately, was
15
associated with a high risk of sudden death and so
16
that the overall benefit of these agents was
17
abrogated by the delayed and unexpected toxic
18
effects.
19
He stated that meta-analyses were really
20
required to adequately validate a surrogate
21
endpoint. That is, even if you
had had a study or
22 two
where there was a significant association
251
1
between a surrogate--progression-free survival, for
2
example, and survival--that you really needed to
3
have a cadre of studies to evaluate that
4
relationship in several different venues to be
5
certain that the surrogate was truly predicting
6
clinical benefit. And he pointed
out that such
7
surrogate markers that are adequately validated are
8
distinctly rare in clinical medicine, but I believe
9 it
was Dr. Williams that pointed out that the FDA
10 has
granted approval using surrogate endpoints that
11
haven't been formally validated, and we saw some
12
examples just a few moment ago in Dr. Ibrahim's
13
presentation.
14
Tom then went on to discuss
15
non-inferiority trials, and I won't belabor this
16
point except to say that there are very important
17
methodological factors that need to be taken into
18
consideration, that it's not enough for the curves
19 to
overlap, you need to be certain that you're not
20
allowing a significant decrease in therapeutic
21
effect in these non-inferiority trials.
And there
22 was
some lack of enthusiasm in general on the part
252
1 of
the panelists that these studies might not truly
2
move the field forward. And the
main area of
3
interest for non-inferiority trials is if there was
4 a
treatment that was substantially less toxic than
5 the
current standard.
6
Then we move on to the last two
7
presentations, which focused on time to tumor
8
progression and disease-free survival for the
9
adjuvant situation, respectively.
This
10
presentation was given by Dr. Langdon Miller. He
11
discussed clinical benefit or the time to tumor
12
progression as a clinical benefit endpoint for
13
first-line metastatic colorectal cancer.
And Dr.
14
Miller took the point of view of making a very
15
strong case for time to tumor progression.
16
He pointed out that in colorectal cancer
17
now, in contradistinction to years gone by, we have
18
multiple therapies that do have benefit in this
19
disease and that it has, therefore, become more
20
difficult to assess the impact on survival because
21 of
these effectiveness therapies that can have an
22
impact on second-line treatment.
Second-line
253
1
treatment can be effective and thereby obscure the
2
relationship between the initial treatment and the
3
ultimate survival of the patient.
4
He argued against the use of symptomatic
5
progression or time to symptom progression because
6
these patients frequently aren't symptomatic to
7
start out with. It's very
subjective and difficult
8 to
measure.
9
He stated from his point of view that time
10 to
tumor progression should be a valid endpoint for
11
full approval in first-line colorectal cancer
12
because this endpoint directly evaluates changes in
13 the
disease burden, that is, regression of tumor or
14
lack of progression of tumor; correlates with other
15
outcomes and, in particular, survival, and I'll
16
show you some data on this point in just a moment.
17 It
has the big advantage that it's not confounded
18 by
subsequent therapies. Second-line
treatment
19
won't affect the time to tumor progression, and he
20
made that point that it offers utility as an
21
endpoint in non-inferiority trials because the
22
sample sizes that would be required would be much
254
1
smaller.
2
He made the point that the endpoint can be
3
objectively quantified, reviewed, and audited by
4
external panels; if you're doing radiographic
5
procedures to document the lack of progression at a
6
particular point in time, offered clear
7
interpretation, straightforward analysis, and
8
certainly would conserve patient resources and
9
hasten drug development.
10
The data that he presented correlating
11
time to tumor progression and survival in
12
first-line metastatic colorectal came from two
13
clinical trials involving 1,000 patients treated
14
with irinotecan-based chemotherapy.
And so he had
15
primary patient data for these 1,000 patients and
16
found a very strong correlation between time to
17
tumor progression and overall survival among these
18
1,000 patients. A Cox analysis
was performed,
19
plugging in all of the important prognostic
20
discriminants, and time to tumor progression was
21
still strongly associated with survival.
22
Secondly, in the questioning session, we
255
1
asked whether any meta-analyses had been done of
2
this surrogate endpoint, and the response was that
3 one
meta-analysis has been performed involving the
4
published summary results of 29 trials involving
5
some 13,000 patients, where there was, again, a
6
highly significant correlation between time to
7
tumor progression and survival, but this was not
8
with the primary individual patient data.
9
This presentation generated a lot of
10
discussion among the panelists.
There was some
11
concern expressed that there really needs to be a
12
very objective and reliable methodology for
13
assessing time to tumor progression.
It's not
14
nearly as definitive as patient survival. But it
15 was
felt that with modern radiologic techniques and
16
external review committees and properly written
17
protocols, that particular barrier could be
18
addressed.
19
There was a lot of discussion regarding
20
whether time to tumor progression reflects clinical
21
benefit in its own right per se, and here I'd say
22
that there was a big disagreement.
There was not
256
1
consensus on the part of the panel.
2
For example, if a patient is asymptomatic
3 and
has metastatic disease, his time to tumor
4
progression is perhaps prolonged by a month or two,
5 but
he experiences very severe toxicity as a result
6 of
the chemotherapy, and the overall survival is
7 not
really changed. How much of a benefit is
that
8 to
the patient? And there was, therefore,
not a
9
consensus on that particular point.
10
Is time to tumor progression reasonably
11
likely to predict clinical benefit based upon the
12
association between TTP and survival?
I think the
13
majority of the panel would feel that would be the
14
case, but also that a more complete gestalt
15
regarding the patient and the clinical circumstance
16
need to be taken into consideration.
We heard that
17
comment earlier today. We're
interested in the
18
response rate, the survival, the toxicity pattern,
19 in
addition to time to tumor progression to really
20
make an overall assessment of the benefit of the
21
treatment for the patient.
22
Then, finally, Dr. Dan Sargent, who is
257
1
here today, gave a preliminary analysis of the
2
correlation between three-year disease-free
3
survival and overall survival as endpoints in
4
evaluating adjuvant therapy for colon cancer. Dan
5
presented the results involving some 12
6
prospectively randomized, Phase II clinical trials
7 in
patients with resectable colon cancer.
There
8 are
some 38 treatment arms involved in these 12
9
trials and more than 10,000 patients involved. And
10 he
did have primary data.
11
The preliminary conclusions of this
12
presentation showed a rather striking correlation
13
between three-year disease-free survival and
14
five-year overall survival. The
event rates, that
15 is,
the number of relapses in three years or the
16
number of deaths within five years, was virtually
17 identical so that whether you used one
endpoint or
18 the
other, this did not have a significant impact
19 on
the sample size. He found that
three-year
20
disease-free survival may slightly overestimate
21
differences in five-year overall survival,
22
particularly in the experimental arms of these
258
1
randomized trials. And there were
three of the
2
studies where there was a statistically significant
3 difference in three-year disease-free survival
at
4
borderline p values, in the range of 0.03 to 0.04,
5 but
no significant difference in five-year overall
6
survival. But the point was made
that some of
7
these trials were not adequately powered to detect
8
differences in overall survival.
And it was also
9
pointed out, I believe by Dr. Fleming, that this
10 was
not a formally validated surrogate.
11
So Dan presented those results as a work
12 in
progress and in just a moment will be presenting
13 an
update of this analysis where he's done
14
considerable additional work since that time.
15
There was discussion among the panel as to
16
whether three-year disease-free survival
17
represented clinical benefit per se in its own
18
right, and there were a number of individuals there
19
that felt this was the case, independent of
20
survival effect.
21
I guess I would express a personal concern
22 that
survival also would need to be evaluated in
259
1
these studies to be certain that there wasn't a
2
delayed adverse impact on survival that wouldn't be
3
seen until some delayed point in time, so you
4
wouldn't want to trade a significant benefit in
5
three-year disease-free survival for a significant
6
decrement in long-term survival.
And it was also
7
pointed out that disease-free survival is used for
8
full approval in breast cancer adjuvant therapy.
9 Why
not in colon cancer?
10
And so, then, to conclude, we bring these
11
questions for your consideration today.
Should the
12
following endpoints be recommended to the FDA for
13 new
drugs in colorectal cancer? And if so,
should
14
they be for full or for accelerated approval?
15
In the colon adjuvant setting, is
16
three-year disease-free survival an appropriate
17
regulatory endpoint? There was
considerable
18
feeling expressed at the workshop that this would
19 be
the case.
20
For first-line metastatic colorectal
21
cancer, is time to tumor progression or
22
progression-free survival an appropriate endpoint?
260
1 And
there was considerable feeling that it was
2
reasonably likely to correlate with clinical
3
benefit.
4
And in the rectal adjuvant setting, should
5
three-year local control, preventing the
6
devastating symptoms from local tumor recurrence be
7 a
regulatory endpoint for new drugs being studied
8 in
the rectal adjuvant setting?
9
Thank you very much.
10
DR. KELSEN: Thank you, Mike.
11
I think this is a very good time to go to
12 Dan
Sargent and hear the update on his analysis.
13
DR. SARGENT: Thank you very
much. I
14
appreciate the opportunity to present updated data
15
today from a meta-analysis exploring the question
16 of
disease-free versus overall survival as an
17
endpoint for adjuvant colon cancer studies.
18
In the setting of colon cancer, it is
19
clear to impact and improve the chance of cure, we
20
must decrease the rate of relapse.
Eighty-five
21
percent of deaths within eight years of diagnosis
22 are
following a recurrence of the cancer, so
261
1
recurrent colon cancer is certainly the primary
2
cause of death in patients who are initially
3
thought to be able to be surgically cured.
4
In addition, due to the devastating
5
consequences of recurrence of disease, prolonging a
6
patient's time without disease certainly should
7
have beneficial impacts on their quality of life.
8
This led us to explore the following
9
hypothesis: that disease-free
survival assessed
10
after three years is an appropriate endpoint to
11
replace overall survival in adjuvant colon cancer
12
trials. The benefits of such a
change would be
13
clear. This would allow the more
rapid completion
14 and
the reporting of clinical trials and, if it
15
held true, would allow promising agents to benefit
16
patients more quickly.
17
In order to assess this question, we have
18
gathered data from multiple large, randomized
19
trials. We have individual
patient data from every
20
trial, and the analyses started out, at least,
21
simple, comparing disease-free survival and overall
22
survival for study arms.
262
1
We've chosen landmark time points of three
2
years for disease-free survival and five years as
3 an
endpoint for overall survival, and you'll see
4
why.
5
In addition to looking on an arm-by-arm
6
basis, we have looked within trials, looking at the
7
difference between the control arm and the
8
experimental arm of each trial to determine if
9
differences that are present on one endpoint are
10
translated over into the other endpoint.
We feel
11
that the most important comparison is the
12
comparison of hazard ratio. That
is, what is the
13
hazard ratio between a control and experimental arm
14 for
disease-free survival? What is the
hazard
15
ratio comparing control to experimental arms for
16
overall survival?
17
To make sure everyone is clear, we used
18 the
following definitions: Overall survival
is the
19
time from randomization to death due to any cause.
20
Disease-free survival is the time from
21
randomization to the first occurrence of either a
22
recurrent event or death. And we
do note that
263
1
second primaries were not included as events in our
2
disease-free survival. Having said
that, the rate
3 of
second primaries is very low, and including them
4 has
almost no impact on these analyses.
5
With respect to the validation of
6
surrogate endpoints, many methods have been
7
proposed, and there is no agreed-upon standard of
8
practice in the statistical community.
Therefore,
9 we
have chosen to examine multiple approaches
10
ranging from simple to complex.
11
The simple approach is to use a weighted
12
linear regression of one endpoint on the other,
13
weighting by the sample size of that trial.
14
Another approach--and I will explain each
15 of
these approaches as I present them--is the
16
Prentice and Freedman approach looking at a
17 quantity
known as the proportion explained. Two
18
other sets of authors--Begg and Leung, and
19
Burzykowski and colleagues--have proposed other
20
methods in Journal of Royal Statistical Society
21
recently, and I will explain those as they are
22
presented.
264
1
On this slide, the trials that are
2
included in the analysis are listed.
We see that
3
they range from first accrual in 1977 all the way
4
down to 1994, so we do span a considerable amount
5 of
time. Many of these trials had
surgery-alone
6
control arms, but some of the later trials had
7
5FU-based treatments in all arms.
Sample size
8
ranged from approximately 250 up to about 2,200;
9
total sample size, close to 13,000 patients, and a
10
total of 33 different treatment arms.
11
Among those 33 arms, there were nine that
12
were surgery-alone control arms and 24 that were
13
considered active treatments in that they were
14
5FU-based.
15
The median follow-up on these patients is
16
eight years, and we have complete data to five
17
years on 93 percent of patients.
And there was
18
some inconsistency among these studies in long-term
19
follow-up, and, therefore, we have censored all
20
analyses at eight years because that was consistent
21
follow-up through eight years in these studies.
22
Just looking at the patient
265
1
characteristics, we can see that most of the
2
patients were between the ages of 50 and 70. About
3 15
percent were over the age of 70, so consistent
4
with the age distribution on clinical trials, but
5
probably skewed younger than the distribution in
6 the
overall population.
7
We had about a 50/50 split on gender; 20
8
percent or so were treated with surgery alone, and
9 the
majority of patients, 62 percent, were Stage
10
III. Stage I patients were
included in one single
11
trial.
12
Turning to some data, here we've got the
13
recurrence rate by six-month intervals from the
14
date of randomization. If we add up
adjacent
15
number of figures, we get recurrence rates by year.
16 So
we can see that in the first year following
17
randomization, approximately 10.5 percent of
18
patients recur; in the second year, it's actually
19 the
highest recurrence rates; adding these numbers,
20 you
get 12.5 percent; and about 7 percent in the
21
third year. After that, the rate
of recurrence
22
falls off rather steeply.
266
1 So, really, the dominant force in
2
recurrent disease happens in the first three years
3
following randomization.
4
We then looked at the time from occurrence
5 to
death, and consistent with data that we've known
6 for
a long time on advanced colon cancer, we have a
7
median time from occurrence to death of about a
8
year. And so patients that recur
by three years
9
very likely will have died by five years.
10
We then looked at the rate of agreement on
11 a
per patient basis for these two endpoints.
So
12
what's shown here--and notice the scale does not go
13 to
zero; it's magnified to show additional
14
detail--is the concordance rate between a
15
disease-free survival endpoint at x years, where x
16
ranges from one up to five, and the overall status
17 at
five years.
18
So what does this mean? If we
look at the
19
three-year time point, we see approximately 90
20
percent agreement between your disease-free
21
survival status at three years and your overall
22
survival status at five years.
And we can see that
267
1
this curve climbs for the first year or two
2
following randomization, but that it really
3
plateaus at about the three-year time point.
4
So that suggested that three years is an
5
appropriate time point to look, and here shown
6
graphically is the simple rate of disease-free
7
survival at three years compared to overall
8
survival at five years. And,
again, notice that
9
these scales are magnified to show additional
10
detail. They do not go from zero
to one. If they
11
did, you'd just see this little crowd in the
12
middle. So we blew them up.
13
Spearman correlation is 0.89, R-squared
14
from our regression is 0.86, both measures
15
indicating significant concordance between these
16 two
effects.
17
Our regression equation result was that
18
overall survival is, in essence, zero plus one
19
times three-year disease-free survival.
Looking at
20 the
p values, we see that the intercept is not
21
significantly different from zero.
The slope is
22
significantly different from zero, but it's not
268
1
significantly different from one.
And so
2
statistically we cannot reject the simple equation
3
that five-year overall survival equals three-year
4
disease-free survival.
5
Within each of the study arms, 33
6
different study arms, the largest difference in
7
absolute numbers was 6 percent between disease-free
8 survival
and overall survival. In 27 of the 33
9
arms, the difference between these two endpoints
10 was
3 percent or smaller.
11
So the first set of conclusions is that on
12 a
patient-by-patient basis, three years does seem a
13
reasonable time point to look.
The recurrence rate
14 is
higher in the first three years and then falls
15
off. The survival following
recurrence is about a
16
year. And the per patient
concordance reaches its
17
peak at about three years and then plateaus. And
18 on
an arm-by-arm basis, three-year disease-free
19
survival from regression modeling is an excellent
20
predictor of five-year overall survival.
21
Perhaps more importantly, we're interested
22 in
the question of: Does a comparison of
study
269
1
arms using disease-free survival reach the same
2
conclusion as if we used overall survival? Because
3
that's what we really want to know:
Does a new
4
treatment do better than an old treatment?
5
In order to do this, we attempted to
6
actually mimic the conduct of the clinical trial
7
because at three years of minimum follow-up--some
8 patients have been on the study for longer
than
9
that. Studies take two or three
years to accrue,
10 and
so three years after the last patient is
11
registered, some patients will have been followed
12 for
four years or five years. And so because
we
13 had
the individual patient data, we attempted to
14
replicate the analysis that would have been
15
completed at the three- and five-year time points
16 to
try to answer the question: What if we
did the
17
analysis at the time that the analysis would have
18
been done, not retrospectively?
19
We also have started to perform analyses
20 at
three years median follow-up as opposed to
21
minimum follow-up, and the conclusions we're
22
reaching are very similar on those endpoints. But
270
1
that is not a completed work.
2
Perhaps the most important slide, at least
3 in
my opinion, this plots the hazard ratios
4
comparing control arm to the experimental arm in
5
each study. On the x axis is the
disease-free
6
survival hazard ratio compared to the overall
7
survival hazard ratio. We see a
very tight
8
concordance. Again, we have a
Spearman rank
9
correlation of 89 percent, and the R-squared from
10 our
regression is 0.87, indicating a tight and
11
consistent relationship between hazard ratios for
12
disease-free and overall survival.
13
The regression equation is that the
14
overall survival hazard ratio is 0.09 plus 93
15
percent times the disease-free survival hazard
16
ratio. If we look at the
parameter estimates, we
17
will again see the intercept is not significantly
18
different from zero. The slope is
significantly
19
different from zero, but not significantly
20
different from one. So, again, we
cannot reject
21
that the hazard ratio for overall survival equals
22 the
hazard ratio for disease-free survival.
271
1
To translate this into some real numbers,
2 I
have the panel on the right, where what's given
3 is
suppose we see a hazard ratio for disease-free
4
survival of 0.6. What does that
suggest for a
5
hazard ratio for overall survival?
And the
6
translation is 0.65, and it ranges across the
7
values of disease-free survival hazard ratios that
8 we
might see. And what we see is the
regression
9
equation suggests a slight attenuation of hazard
10
ratios from the disease-free survival to the
11
overall survival towards one. But
it's a slight
12
attenuation, on the order of about 10 to 15
13
percent. And I'll describe this
grade in more
14
detail.
15
For the statisticians in the audience, now
16 I
get to have some fun, if that's your idea of fun.
17
Looking at some formal measures of
18
surrogacy, the proportion explained was proposed by
19
Freedman in 1992 as follow-up work to work by
20
Prentice in 1989. In essence,
this approach fits
21 two
Cox regression survival models--one without the
22
surrogate endpoint included, one with the surrogate
272
1
endpoint included.
2
If the surrogate is truly related to the
3
outcome of interest, the surrogate should explain
4
most of the variability in that model.
And so what
5 they
propose to do is look at the proportion of
6
treatment effect explained by the surrogate, and if
7 the
surrogate explains close to 100 percent of the
8
variability, if they presume the surrogate, that
9
would imply that it is a good surrogate.
10
This measure has been criticized by
11
several authors for many reasons, one of which is
12
that it's not actually a true proportion and it's
13 not
bounded between zero and one.
Nonetheless,
14
this is probably the most common method used, and
15 so
we fit that to this data set.
16
Here are the results from the two models.
17
Looking first without disease-free survival as an
18
endpoint, as a surrogate in the model for overall
19 survival,
this is the log hazard ratio indicating a
20
very significant benefit for treatment when
21
disease-free survival is not included a parameter
22 in
the model. When disease-free survival is
273
1
included as a parameter in the model, the p value
2
becomes non-significant, indicating that the
3
disease-free survival is explaining almost all of
4 the
variability in the endpoint.
5
When you calculate the proportion, you
6
actually come up with 138 percent, validating the
7
criticism of this measure that it's not a true
8
proportion. Nonetheless, this
does imply that
9
disease-free survival may be a good surrogate for
10
overall survival.
11
A more sophisticated approach was
12
recommended by Burzykowski and colleagues in 2001,
13
where they fit a bivariate copula survivor model,
14
which, in essence, fits the survival model
15
using--examines the effect of a set of covariates
16 on
both endpoints of interest. And if the
effect
17 of
the covariates on both endpoints is similar,
18
that suggests that the two endpoints themselves are
19
similar. And so they defined two
measures, a trial
20
level R-squared to look at the concordance between
21
endpoints on a trial-by-trial level, and an
22
individual level to look at the per patient
274
1
concordance. And values close to
one for both
2
measures indicate surrogacy.
3
The results applied to this data set have
4 an
R-squared value of 0.85, confidence interval of
5
0.72 to 0.99, and at an individual level we have a
6
concordance measure of 0.9.
7
How to interpret these results.
In the
8
paper that Burzykowski and colleagues published,
9
they had an example from ovarian cancer, and they
10
actually had values of R-squared and TAO very close
11 to
these values in their example. And their
12
conclusion was that it seems plausible to conclude
13
that this is a valid surrogate given the values
14
that we see here.
15
This is a graphical representation of that
16
method looking at the impact on disease-free
17
survival time compared to the impact on overall
18
survival time. These are log
hazard ratios. The
19
size of the circle is proportional to the sample
20
size of the trial. Again, we see
high, tight
21
concordance between the two measures using this
22
sophisticated model.
275
1
Finally, an approach I really tend to
2
prefer, Begg and Leung gave a very simple measure.
3 The
validity of a surrogate endpoint should be
4
judged by the probability that the trial results
5
based on the surrogate endpoint alone are
6
concordant with the trial results that would be
7
obtained if the true endpoint were observed and
8
used. Simple, straightforward, do
they give the
9
same conclusion? Who needs fancy
statistics?
10
Of 18 total within-trial comparisons, we
11
compared the two arms using the endpoint of
12
disease-free survival, using the endpoint of
13
overall survival, log rank testing.
Straightforward, as
14
simple as we can get.
15
Of the 18, 16 gave the same conclusion
16
regardless of which endpoint you used.
Eleven
17
trials had no difference between the two arms for
18
either endpoint; five had significant differences
19
between arms for both endpoints.
20
There were two trials that were
21
significant only for disease-free survival, but
22
both of these had p values of 0.03, so only
276
1
marginal significance for disease-free survival.
2
That is shown graphically on this slide
3
where for each of the 18 trials we have plotted in
4
yellow the disease-free survival estimate and
5
confidence interval, and in blue the overall
6
survival confidence interval and estimate. And as
7 you
go in sets of two, you'll notice how similar
8
within a trial the confidence interval and the
9
estimates are for these two endpoints.
10
If you look more closely, you will see
11
that most of the time the blue dot is a little
12
closer to one than the yellow dot.
What does that
13
mean? It means that we have a
slight attenuation
14 of
the effect, that the hazard ratio for
15
disease-free survival is a little bit farther away
16
from one than the hazard ratio for overall
17
survival. But, again, this
attenuation is very
18
slight, and that's consistent as you go down the
19
plot.
20
Focusing on two trials in particular, one
21 of
the comparison within the trial, NSABPC-04, and
22 the
other was an NCCTG trial from 1978, these were
277
1 the
two trials where the disease-free survival
2
hazard ratio, confidence interval, you can see that
3 it
excluded one, and it was significant.
And for
4 the
overall survival, it included one, thus was not
5
significant. And that's the same
here. But you
6 can
see in both cases the disease-free survival
7
hazard ratio got very close to one, and the overall
8
survival hazard ratio hardly excluded one. So the
9
results are really consistent with each other, and
10
what we ran into was just a little bore edge effect
11
there.
12
So the second set of conclusions.
As an
13
endpoint for comparison, the hazard ratio for
14
disease-free survival is an excellent predictor of
15 the
hazard ratio for the overall survival with a
16
slight attenuation. Marginally
significant
17
improvements in disease-free survival may not
18
translate into overall survival.
The formal
19
measures that we have assessed do suggest surrogacy
20 is
appropriate for these two endpoints.
21
How to translate this into something that
22 can
be helpful and useful to the practicing
278
1
clinician--at least I hope. Let's
suppose in a
2
trial of 2,000 patients we observed a disease-free
3
survival hazard ratio of 0.8.
Using our model, you
4 can
translate this into a predicted hazard ratio
5 for
overall survival of 0.84. So we see that
6
slight attenuation.
7
In addition, we can compute a 95-percent
8
predicted interval for the hazard ratio for overall
9
survival. In this case, it would
go very 0.77 to
10
0.91. So in this case of a trial
of 2,000, if you
11
observe 0.8, you're 95-percent prediction interval
12 for
overall survival would exclude one.
13
We can do this not only for a value of
14 0.8,
but we can do it for any observed value of
15
disease-free survival and calculate bounds like
16
this. Now, of course, that
depends on the sample
17
size from your trial. This
example used 2,000
18
patients. If we instead use 1,000
patients--and
19
these red lines are a little bit hard to see, but
20 we
can see that the lines fall outside the lines
21 for
1,000. They get wider. The prediction
22
interval is wider. And if you
have a trial for
279
1
3,000 patients, the blue bands get narrower. So
2
based on the sample size, we can see how sure we
3 can
be about our prediction.
4
Now, suppose we want to be sure--and I
5 apologize,
these red lines show up much better on
6 my
screen than they do here. Maybe I'll
just go to
7 the
yellow line. Okay.
8
Suppose that we want to ensure that our
9
overall survival hazard ratio--that the prediction
10
interval for our overall survival hazard ratio
11
excludes one. What we can do is
go across the line
12 and
come down, and notice that if our observed
13
disease-free survival hazard ratio is less than
14
0.90, our predicted interval for our overall
15
survival hazard ratio will exclude one.
And, also,
16 for
the case of 3,000, you can just calibrate it as
17 you
see fit.
18
In order to test the validity of this
19
model, we have performed leave-one-out
20
cross-validation. What does that
mean? It means
21 of
the 18 comparisons, we took one out at a time,
22 fit
the model to the 17 that remained, used the
280
1
data from those 17 to predict what happens in the
2
trial that we did not include in our model, and
3
then see if the model based on the 17 predicts well
4 on
the one that we did not include their data.
5
Shown here in the blue dots are the
6
predicted hazard ratio for overall survival based
7 on
disease-free survival. In the red are
the
8
actual results. And we can see
that for 17 of the
9 18
trials, the actual result fell with the
10
95-percent prediction intervals.
This is exactly
11
what we would expect. If we have
18 and we're
12
computing 95-percent confidence intervals, one of
13
them should fall outside. Here it
is. It fell
14
outside, but just by a little bit.
Also notice
15
that sometimes the actual, which are the red, are
16
above the blues; sometimes they're below the blues.
17 So
this indicates that the model is calibrated well
18 and
is predicting accurately.
19
Turning to a few points for discussion, we
20 did
have individual patient data from all of our
21
trials. All of these trials used
5FU-based
22
regimens. They did includes a
mixture of Stage III
281
1 and
Stage II patients. Our preliminary work
2
suggests that the concordance is somewhat stronger
3 for
Stage III than it is for Stage II.
That's not
4
surprising because recurrences would happen more
5
quickly in Stage III than in Stage II.
But we're
6
doing further analyses on that point, but we do
7
feel that for trials similar to those that were
8
included here, which included a mixture of Stage II
9 and
Stage III, these results should be relevant.
10
I think open for discussion is issues
11
about how relevant this is to the current practice.
12 For
example, we now have more advanced--more
13
effective therapies available in the advanced
14
disease setting. We've improved
the median
15 survival
from 12 months to 18 to 20 months.
Having
16
said that, most people who recur by year three
17
still die by year five.
18
In addition, we have improved methods for
19
detection of occurrence with improved imaging
20 techniques,
so perhaps recurrences are being
21
detected earlier in a more curative state.
22
I think it's also open for discussion what
282
1
about non-cytotoxic or targeted agents.
Perhaps
2
instead of preventing a recurrence, perhaps just
3
delay a recurrence. And if such
agents are
4
available, the concordance between these endpoints
5
could decrease. Or maybe we just
need to look at
6 different
time points.
7
Conclusions are that for the studies we've
8
examined, disease-free survival is an excellent
9
predictor of overall survival. It
meets most
10
formal definitions of surrogacy.
There is a modest
11 attenuation
of treatment effect between these two
12
endpoints on the order of 10 to 15 percent. And
13 the
model allows prediction of the benefit on
14
overall survival based on what we observe for
15
disease-free survival.
16
I close by acknowledging my many
17
collaborators from around the world on this project
18 and
put in a plug. This is still not the
final
19
analysis that will be done. We
have recently in
20 the
last few weeks gained data from three
21
additional large trials. It will
be included in
22 the
analysis to be presented at ASCO in June of
283
1
this year, and I did want to note that I did
2
receive permission from ASCO to present this
3
material at this meeting today.
4
Thank you very much.
5
DR. KELSEN: Thank you, Dr.
Sargent.
6
So at this point we'll open the floor for
7
questions to any of the four presenters, questions
8
from the panel.
9
DR. GEORGE: You started off
giving a nice
10
presentation of why three-year disease-free
11
survival, how it relates to five-year overall
12
survival, and then you seemed to kind of drop that
13 as
you got further into it, talking about hazard
14
ratios, which I assume were based on estimates from
15 the
whole data, not just restricted to three years
16 and
five years. Is that true?
17
DR. SARGENT: No, they were--the
hazard
18
ratios for disease-free survival were calculated
19
using only the data from the first three years.
20
DR. GEORGE: And despite your
elegant
21
arguments for why that seems to work well, why
22
would you not use all the data?
Is this just a
284
1
pragmatic thing that you want to be able to predict
2 it
earlier?
3
DR. SARGENT: The question was not
so much
4 from
an academic standpoint as it was--we have
5
to--we took a pragmatic approach.
We have to do an
6
analysis at a certain time point.
You analyze a
7
trial, and the question is when can we analyze a
8
trial. And really, the goal
is: Can we analyze a
9
trial more quickly?
10
And so if we're able to analyze a trial
11
earlier and reach the same conclusions if we
12
analyzed it later, that was something that we
13
sought to show.
14
DR. GEORGE: But the thing that's
still
15
puzzling me about this is the three-year
16
disease-free survival is sort of--it's like a per
17
patient analysis, is it not? That
is, you're
18
really looking at, on each patient, whether--what's
19 the
chance of making it to the three years
20
disease-free survival. It's not
three years
21
calendar time from the time you start the study,
22
because they're two different things.
285
1
DR. SARGENT: That is
correct. For the
2
first set of analyses, which were on the per
3
patient basis, it was to establish is three years a
4
reasonable time point to look within a patient.
5
Then we turned our attention to what happens when
6 you
actually analyze the trial, and you have to
7
analyze the trial at a certain time point, and we
8
chose what if we analyzed the trial at the
9
three-year time point using data from all the
10 patients,
and if the patient had four years because
11
they were entered earlier, taking advantage of that
12
data.
13
So the first set of analyses was really to
14
establish that three years is a sensible time point
15 to
look on a per patient basis, and then that was
16
supported then later by is three years a sensible
17
time point to look on a per trial basis.
18
DR. KELSEN: Dr. Brawley?
19
DR. BRAWLEY: Dr. Sargent, I want
to
20
congratulate you. I just sat
through a statistics
21
lecture, and I actually think I understand it.
22
Maybe I need a head CT.
286
1
[Laughter.]
2
DR. BRAWLEY: The question
is: You make a
3
very strong argument for use of disease-free
4
survival as a surrogate for overall survival when
5
using anti-neoplastic agents. Can
you speculate on
6 how
well this model would translate if we were to
7
start looking at things like growth factor
8
inhibitors, where instead of looking at
9
disease-free survival we would be looking at things
10
like progression-free survival?
11
DR. SARGENT: I really don't feel
12 comfortable
extrapolating beyond the range of the
13
data and the trials that we included in the
14
analysis. Thank you.
15
DR. KELSEN: Dr. Redman?
16
DR. REDMAN: Something along
similar lines
17 to
that. With the model that you have set
up, if
18 we
now go out five years from now--and I don't know
19
what's going to be happening, but if we now know
20
that the median survival for advanced or recurrent
21
colorectal cancer goes out to 24 or 30 months, do
22 you
think this model will still hold? Or the
other
287
1
question also is if we then push the time to
2
relapse out with therapies.
3
DR. SARGENT: Regarding the first
4
question, I think the model will be less sensitive
5 to
that because the magnitude--the advances that
6
have been made in advanced colorectal cancer are
7
wonderful. In absolute magnitude,
they're still
8
modest. And so if we increased
the median survival
9
from one year to two years, the reality is everyone
10 who
recurs year one, everyone who recurs year two,
11 and
most of the people who still recur in year
12
three will still have an unfortunate outcome of
13
death by year five. And so I
think we need to have
14 a
pretty profound impact on survival in the
15
advanced disease setting to translate into this
16
model.
17
Having said that, it may be that we have
18 to
look at a later time point, and I think we have
19 the
opportunity with the collaboration that we've
20
established and the data that we have, we've
21
already been pledged to have data from some of the
22 new
trials when they become available. I
think, of
288
1
course, the challenge is the five-year data is not
2
available from those trials.
3
With respect to the second question, I
4 think
that's more up in the air. I think if
5
recurrences are simply delayed as opposed to
6
prevented, then I--and recurrences start happening
7
more frequently out in the fourth year and the
8
fifth year, then I think that could have some
9
pretty serious consequences to the validity of this
10
model, and it would need to be assessed again for
11
those different agents.
12
I think Ross Prentice in his seminal work
13 on
this topic has made the point that a surrogate
14 is
really relevant and related to the treatments
15
that are being used, and if treatments are used
16
that have different mechanisms of action or
17
influence the endpoints in different ways, then the
18
surrogate endpoint that had been previously
19
validated may not be considered valid anymore and
20
would need to be re-validated for that new set of
21
agents.
22
DR. KELSEN: Dr. Martino?
289
1
DR. MARTINO: Two questions, I
think both
2 to
Dr. Sargent, but the rest of you may chime in.
3
First of all, I'm not sure that I now
4
understand when you say three years, what we're
5
counting from. So explain that to
me first.
6
DR. SARGENT: Okay. We've done two sets
7 of
analysis. One is on a per patient basis,
and
8
that is three years from the date that they are
9
enrolled in the trial
10
DR. MARTINO: Okay.
11
DR. SARGENT: The second set of
analysis
12 is
on the trial-by-trial basis, and that is doing
13 an
analysis--presuming that we perform our primary
14
analysis at the time point three years after the
15
first--excuse me, after the last patient is
16
enrolled. So we have three years
minimum follow-up
17 on
all patients, but some patients may have four
18
years, some patients may have five years, because
19
they entered the trial earlier.
20 DR. MARTINO: And so which of those are
21 you
advising to this group? That's what I'm
not
22
clear on.
290
1
DR. SARGENT: Okay. I think what's
2
relevant primarily for this group--I'm not advising
3
anybody. I'm just presenting
data. But I think
4
from this committee's perspective, if I was sitting
5 on
the committee, you see data presented by a
6
sponsor that compares two trials arms--a control
7 arm
and an experimental arm--and that's an analysis
8
that's done with a specific endpoint at a specific
9
time point. And I would suggest,
based on this
10
data, that for the type of agents that have been
11
explored in this analysis, an analysis that's
12
presented on disease-free survival three years
13
following the entry of the last patient on study is
14 an
excellent predictor of an analysis that may be
15
subsequently presented to this committee at a time
16
point five years after the last patient is entered
17 and
on an endpoint of overall survival.
18
DR. MARTINO: Now, the other way
that I've
19
seen this type of data presented, predominantly in
20
breast cancer, is that one actually specifies how
21
many events you want to see, and then when those
22
have occurred, you use that as the time point at
291
1
which you compare two arms. I
need your thoughts
2 on
that way of doing things.
3
DR. SARGENT: Okay. That's an excellent
4
point.
5
The time points are all related to the
6
minimum duration of follow-up, and what this, in
7
essence, presumes, if I was a sponsor organizing a
8
trial, I would design my trial and design my
9
hypothesis tests so that the number of events
10
necessary to provide my power became available at
11 the
time we projected the last patient would have
12
been followed for three years.
And so this is all
13
presuming that we have enough events to power our
14
trial appropriately.
15
DR. MARTINO: Okay. And that gets me to
16 my
final question. As has happened in breast
17
cancer in the adjuvant setting, I anticipate a
18
similar behavior will occur in colon cancer, which
19 is
that as you have a few more agents that appear
20 to
work in the metastatic setting, you now to start
21 to
ask adjuvant questions in patients with lesser
22 and
lesser disease. And so presumably now a
292
1
three-year endpoint, however one defines that
2
three-year, might encompass most of the
3 recurrences.
But as you start to look at lesser
4 and
lesser disease, that three-year won't quite be
5 the
same. You may have to wait for five
years for
6
patients with little disease to recur for you to
7
then capture 80 percent or whatever percent of them
8 you
want.
9
So if I'm understanding that correctly,
10
then whatever decision is made today may be less
11
applicable with the passage of time, and that time
12
might be even two years from now.
13
Do you understand my question? Am
I
14
making sense?
15
DR. SARGENT: Yes,
absolutely. So to
16
comment on that, I think that the results that I've
17
presented today are relevant to trials that would
18 be
conducted with a similar patient population as
19
were included in these trials.
And these trials
20
included a mixture of Stage II and Stage III
21
patients. It was actually quite
consistent, about
22 a
60/40 to 50/50 split between Stage II and Stage
293
1
III's. I think in a study of just
Stage II
2
patients, these particular data may be less
3
relevant. However, we have
individual patient
4
data. We are performing the
analyses in just the
5
Stage II patients and in just the Stage III
6
patients to see if the concordance is as strong in
7
each group. And as I stated, our
preliminary
8
results are that the concordance is stronger in the
9
Stage III patients than it is in the Stage II
10
patients. But having said that,
if a trial has
11
about this mix of patients, I think these results
12
would hold valid.
13
DR. KELSEN: Ms. Roach?
14
MS. ROACH: First of all, I saw
this
15
presentation in November, and it was fascinating to
16 see
the work that was done since then. So
thank
17
you.
18
I have two questions, and both of them are
19
pretty straightforward. If and
when someone comes
20
forward with a proposal for a trial for, say,
21
Avastin and a 5FU-based regime for Stage III
22
patients to delay and/or prevent recurrence, then
294
1 are
you saying that this--they might be able to
2
think about disease-free survival, but really,
3
overall survival would need to be the endpoint on
4
that because of the use of a biologic.
5
DR. SARGENT: Well, I think I have
a
6
comment and a response.
7
The comment is that I think it's up for
8
this committee to decide two questions.
One is:
9 Is
disease-free survival a surrogate for overall
10
survival? But I think the other
question is: Is
11
disease-free survival an important endpoint on its
12 own
regard, irregardless of its relationship with
13
overall survival?
14
And so if this committee feels that
15
disease-free survival is an important endpoint on
16 its
own, then I think the question becomes less
17
relevant.
18
With respect to, though, if the endpoint
19 of
disease-free survival is only felt to be valid
20 due
to its surrogacy or due to its relationship
21 with
five-year overall survival, then I do not
22
believe this data would provide a support for that
295
1
surrogacy to hold with this different class of
2
agents.
3
MS. ROACH: Okay.
And then my second
4
question is: Can you keep this
going? You've
5
started something really (?) here, and so how do
6 you
keep it so that in ten years it's not
7
completely useless?
8
DR. SARGENT: Well, we've already
9
established collaborations with many investigators,
10
including the new trials that have been done with
11
irinotecan and oxaliplatin in the adjuvant setting.
12
Both of those investigative groups have agreed to
13
participate in this analysis, and so we'll be able
14 to
update our analysis there. And at that
time,
15
that's all that there is out there.
The biologics
16 are
just entering the adjuvant trials, and so it
17
will be, you know, eight years really until that
18
data is available, presuming they accrue for three
19
years and have five years additional follow-up.
20
So I think that those questions are very
21
relevant; however, I don't anticipate this
22 committee would be seeing any such data for
quite
296
1
some time.
2
DR. KELSEN: Dr. Brawley had a
follow-up
3
question.
4
DR. BRAWLEY: Yes, part of which
has been
5
answered. Dr. Sargent would you
agree with the
6
point that the correlation between disease-free
7
survival and overall survival is a much tighter
8
correlation than, say, as you apply years to it,
9
especially when you look at the stage issue?
10
What I'm trying to say, in short, in as
11 few
words as possible, is as stage goes down, maybe
12
disease-free survival needs to go up.
But it can
13
still maintain a good correlation with overall
14
survival.
15
DR. SARGENT: I think that there
are two
16
factors that relate to that. One
is, as the stage
17
goes down, the time to recurrence probably goes up.
18 The
second is that, as the stage goes down, fewer
19 of
the deaths are due to the cancer and more are
20 due
to other causes. And so I think, A, the
time
21
point may differ for earlier-stage cancers, that we
22 may
have to look at three or four or five years
297
1
because recurrences are later.
And, second, my
2
expectation--and I don't have data to support
3
this--is that the attenuation of the effect may be
4
larger due to a greater proportion of deaths due to
5
competing causes.
6
DR. KELSEN: It may be as stage
goes down
7
that it's not time to recurrence changes; absolute
8
cure rate is higher, and the model for breast
9
cancer may not be 100-percent valid.
And so time
10 to
a non-cancer-related event may be much more of
11 an
issue.
12
Other questions? Yes, Dr.
Rodriguez?
13
DR. RODRIGUEZ: I know that we
were
14
focusing on the analysis of correlation of
15
disease-free survival with overall survival, but I
16
also noticed that, you know, this covers a wide
17
range of time frame for the studies.
And I noticed
18
that the design of the studies keeps shifting from
19
initially the control arm being surgery only, now
20 to
arms using 5FU. So are you seeing a
trend in
21
this meta-analysis for longer disease-free
22
survival, even as the complexity of the adjuvant
298
1
treatments increases? Is that
true or not?
2
DR. SARGENT: Well, we have--two
responses
3 to
that, I guess.
4
First is that we have explored the
5
validity of the relationship over time.
And has
6 the
relationship between disease-free survival and
7
overall survival changed over time?
The answer to
8
that one is no. That has been
very consistent.
9
And, in fact, if you so desired, I could go and
10
show that on a slide, the slide of the hazard
11
ratios--maybe I don't have that.
I think I do have
12
that slide in there, actually.
13
But related to your specific question, I
14
think, is have we seen over time the absolute
15
benefit, and we've actually tried to stay away from
16
such an analysis because that involves comparisons
17 of
non-randomized arms to each other.
Nonetheless,
18
that is something that we have observed, that the
19
survival rates for either disease-free or overall
20
survival from the trials performed in the early
21
1980s compared to the trials that have become
22
mature in the late 1990s, though the overall
299
1
survival and disease-free survival rates certainly
2
have improved over time, is that due to better
3
treatments? Is that due to better
staging? Is
4
that due to better supportive care?
Is that due to
5
better surgery? We don't
know. And so we have
6
stayed away, actually, from making those sorts of
7
comparisons of absolute treatment effects over
8
time--excuse me, of absolute survivals over time.
9
What we've focused on is the treatment effect over
10
time, and is the treatment effect, comparing the
11
treatment arm to the control arm, consistent--which
12 it
is.
13
I hope that answered the question.
Thank
14
you.
15
DR. KELSEN: Dr. Cheson?
16
DR. CHESON: To ask a somewhat
naive
17 question falling under the category of
"we should
18 be
so lucky," but if we were to develop a much more
19
effective treatment for relapsed patients, how
20
would that impact on this? And
how do you take
21
into account the fact that this new therapy may
22
have some sort of interaction with the initial
300
1
therapy, either positive or negative?
Meaning it's
2
going to work if you had x, but it's not going to
3
work if you had y.
4
DR. SARGENT: Well, I think it is
5
important to note that if we could triple the
6
survival following recurrence, I think that would
7
have an impact. I think, you
know, in terms of the
8 time
points we're looking at, we're looking at a
9
two-year window between the three-year time point
10 and
the five-year time point.
11
Once we start pushing the median survival
12
following occurrence out past that two-year window,
13
then I think it could really have a bigger impact
14 on
these results. We haven't seen that yet.
15
Hopefully we will.
16
With respect to interaction between the
17
treatment they received first and the treatment
18 they received subsequently, we only have data
on
19
patients who were treated with a 5FU-based sort of
20
thing initially. And I guess I
really can't
21
speculate as to if patients are treated with some
22
other sort of agent up front.
301
1
DR. KELSEN: I have a question for
FDA,
2 for
Dr. Ibrahim, related to using other tumors as a
3
model. In breast cancer,
three-year disease-free
4
survival is recognized for approval of a new agent
5 in
the adjuvant setting as opposed to colon cancer,
6
talking about today, and I think that you said it
7 was
because breast cancer recurrences were
8
symptomatic. Does that apply to
both hormonal
9
therapy as well as cytotoxic therapy?
And is it
10
correct that the rationale for using three-year
11
disease-free survival in breast cancer was based on
12 the
fact that women would be more likely to be
13
symptomatic from a recurrence than, say, a man or a
14
woman who has colon cancer? And
is that still true
15
with modern imaging today?
16
DR. IBRAHIM: I'm not sure I can
answer
17
that question. Maybe Rick or
Grant--
18
DR. PAZDUR: Our opinion regarding
breast
19
cancer, which occurred many, many, many years ago,
20 was
based on the fact that it was believed that
21
these recurrences were symptomatic.
Okay? Whether
22 one
wants to believe that now or not believe it
302
1
with introductions of other imaging, closer
2
follow-up of patients, et cetera, is open to
3
discussion.
4
I don't know how much relevance that has
5 here because I would see that the vast
majority of
6
recurrences from colorectal carcinoma, especially
7 as
our follow-up of patients and our radiographic
8
imaging becomes better and more intense, that most
9 of
these recurrences are not symptomatic.
So it's
10 a
little bit different situation. I don't
11
necessarily think we have to rely on that it's
12
occurred many years ago. I
wouldn't use that as
13 any
regulatory precedent that we use that basis,
14 because
I don't even know if it would hold at this
15
time. Perhaps Silvana would like
to comment on
16
recurrences and symptoms.
17
DR. MARTINO: Well, a couple of
thoughts,
18
Rick, because this is one of my issues as well. My
19
impression is that sometimes the FDA has accepted
20
three-year disease-free events, but for the most
21
part, we tend to pilot things to five years, not to
22
three, when we do, you know, large, intergroup sort
303
1 of
trials. So I'm not sure that three years
is
2
where you've given most of the approvals in breast
3
cancer. I believe it is closer to
five. Number
4
one. Okay?
5
But relative--so that's that.
Okay.
6
Relative to patients becoming symptomatic,
7 I
don't think that that biology has changed.
When
8 a
patient with breast cancer recurs, she generally
9 is
symptomatic, because often what drives the
10
x-rays that you are going to do are, in fact,
11
symptoms. Very rarely is it
something else.
12
I don't understand the biology of colon
13
cancer well enough--because this is what's going
14
through my mind, is I keep hearing several of you
15 who
deal with colon cancer using this expression
16
that they're asymptomatic. And
I'm assuming what
17
that means is they've got something in the liver,
18 for
the most part, and it's not causing them a new
19 problem,
though I'm not sure how you figured it out
20
that they had it in the first place.
But there
21
must be some time point where they do become
22
symptomatic, and one of the things I need to
304
1
personally understand as I think about disease-free
2
survival as a valuable endpoint onto its own,
3
exclusive of survival, is if you do have this
4
asymptomatic colon in a recurrent patient, is there
5 some
time span when you can say, well, within a
6
year most of them are going to be symptomatic,
7
anyway? Is there such an
understanding
8
biologically?
9
DR. KELSEN: Dr. O'Connell and I
will both
10
address that. I think Dan pointed
out, first of
11
all, that the time to death from recurrence prior
12 to
newer agents is about a year.
13
DR. MARTINO: But it's not time to
death
14 I'm
interested in--
15
DR. O'CONNELL: It's time to
symptomatic
16
progression, and there have been studies done in
17
patients with known metastatic colorectal cancer
18 who
were asymptomatic at the point of beginning the
19
observations, and this was worked on by Dr.
20
Moertel. The median time to
progression is about
21
five months, and 80 percent of patients were
22
symptomatic within one year. But
the median was
305
1
five months.
2
DR. MARTINO: So there is a
reasonable
3
correlation there that if you recur within that
4
year, 80 percent will be symptomatic.
5
DR. O'CONNELL: Yes.
6
DR. MARTINO: So to me--and this
becomes
7 the
issue in terms of is overall survival the only
8
objective that we should be aiming for, because it
9
strikes me that if symptoms follow reliably to that
10
degree, that disease-free-ness is important.
11
DR. O'CONNELL: Yes.
12
DR. MARTINO: And is important all by
13
itself. The other is wonderful,
but it doesn't
14
obviate that there's value in being disease-free
15
because you will become symptomatic within a
16
reasonable short period of time.
17
DR. O'CONNELL: I agree.
18
DR. KELSEN: Ms. Roach?
19
MS. ROACH: I have a follow-up
question on
20
that. What is the typical
timeline, in your
21
judgment, between symptomatic progression--the
22
development of symptoms and then death?
306
1
DR. KELSEN: I think Dr. O'Connell
2
commented on this. There are
several trials, not a
3
large number of randomized studies of no treatment
4
versus immediate treatment, which gave the
5
symptoms, the Nordic trial and several others, and
6 the
time frames were exactly what Mike said.
7
DR. O'CONNELL: Actually, Dr.
Miller
8
presented some data at a workshop as well that if
9 one
looked at the point in time from progression,
10
with advanced metastatic disease progressing, to
11 the
time of death, it's about eight months, and
12
with salvage therapy out to 11 months or so. So,
13 again,
there's a period of several months from the
14
time of developing symptoms until death.
And I
15
guess it wasn't precisely symptomatic progression
16
that Langdon was talking about.
It was any
17
progression. The median time was
eight months from
18 the
detection of any progression from metastatic
19
disease, whether symptomatic or not, and death.
20 And
so presumably it would be shorter than that if
21 it
was asymptomatic progression, coming back to
22
about the five- to six-month range again.
307
1
DR. KELSEN: Dr. Hirschfeld, you
had a
2
question?
3
DR. HIRSCHFELD: I have a question
for Dr.
4
Sargent, and I, too, want to congratulate you on
5 the
initiative of this very intriguing analysis.
6
Several of our colleagues around the table have
7
pointed out the potential limitations of the
8
analysis with regard to types of therapy, types of
9
products. We're particularly
interested in
10
immunotherapies, among others.
But we haven't yet
11
discussed alterations in how one measures
12
progression, and there have been a lot of
13
developments in looking at PET scans and other
14
types of imaging techniques, as well as other
15
potential techniques.
16
So to maintain the interest and to follow
17 Ms.
Roach's suggestion of having this as an ongoing
18
project, what other types of analyses then would
19 you
entertain or explore to look at disease-free
20
survival and overall survival, other than your
21
landmark analyses, which has been pointed out is a
22
shifting target already?
308
1
DR. SARGENT: Well, I think the
trials
2
that were conducted and included in this analysis
3
were conducted in, for the most part, the pre-PET
4 era
and had very protocolized follow-up. And
so I
5 guess
what further analysis would we conduct, I
6
think we would want to look now--once we look at
7
some new trials--at the method of assessment of the
8
recurrence and is it true that, say, PET-detected
9
recurrences are as highly correlated with survival
10 as
non--as physically detected or x-ray or CT.
I
11
think the new trials actually provide much richer
12
data sets than many of these older trials that
13
collected very much bare-bones sort of approaches.
14 And
so I do think there will be a number of
15
additional pieces of information that we can look
16 at.
17
With respect to immunotherapies in
18
particular, I guess the jury is still out, and we
19
have to get some actual data on five-year
20
assessment with those therapies.
21
DR. KELSEN: Dr. Pazdur?
22
DR. PAZDUR: I think, you know,
several
309
1
people have brought up, well, what if our
2
evaluation techniques change?
What if the drugs
3
change? God knows. Okay?
4
As a discussion here, I think we have to
5
point out where we are now.
Obviously, we can
6
always reassess where we're going to and what
7
changes will be impacted. But I
kind of want to
8
direct the attention and the flow of the
9
discussion, because we have a lot of material to
10
cover here, toward what we have at hand.
We could
11
always talk about what will be a new improvement in
12 ten
years or five years, what will be the role of
13 PET
scanning, what will be the role of this and
14
that. That will impact--then we
as a regulatory
15
agency have to make that decision.
16
I'll just parenthetically
add that, even
17
though we are allured by new mechanisms of actions
18 of
drugs, many times, at least in the advanced
19
disease, we've seen very consistent effects on
20
established endpoints--Avastin, for example, having
21 a
consistent effect on our ways of measuring
22
anti-tumor activities or response rate improvement
310
1 and
improvement in time to progression or
2
improvement in survival.
3
So even though drugs may have a different
4
mechanism of action--and, granted, it's in the
5
advanced disease--they still may ultimately express
6
their effect on more conventional endpoints. But
7 here, again, I think our time is somewhat
limited
8
here, and we could go off and hypothesize in
9
multiple different directions.
But we're here,
10
we're working in 2004, and let's keep the
11
discussion to that and move forward.
12 DR. KELSEN: Any other questions of the
13
panel? Dr. Brawley?
14
DR. BRAWLEY: In follow-up to what
Dr.
15
Pazdur just said, because there are some points
16
that I had, if you look back over the last 30
17
years, you've got a number of trials as technology
18 has
changed over time. Lead-time bias has
been
19
introduced with each introduction of each new
20
technology. Even within CT scan
generations, we've
21
increased lead-time bias.
22 The randomization and the fact that the
311
1
trial is all being done at the same time has always
2
sort of equalized that, and the one thing that we
3 can
do, Rick, is look backward and we can see that
4 the
development of CT scan, the introduction of MRI
5 and
so far the introduction of PET scan has not
6
really changed disease-free survival as a good
7
correlate for overall survival.
8
DR. KELSEN: Any other questions from the
9
panel or from FDA?
10
[No response.]
11
DR. KELSEN: If not, we'll then go
to the
12
open public hearing portion, and there is one
13
speaker, I believe Mr. Carroll. Before
we have Mr.
14
Carroll's comments, both the Food and Drug
15
Administration and the public believe in a
16
transparent process for information gathering and
17
decisionmaking. To ensure such
transparency at the
18
open public hearing session of the Advisory Board,
19 the
FDA believes it is important to understand the
20
context of an individual's presentation.
For this
21
reason, FDA encourages you, the open public hearing
22
speaker, at the beginning of your written or oral
312
1
statement to advise the committee of any financial
2
relationship that you may have with any company or
3 any
group that's likely to be impacted by the topic
4 of
this meeting.
5
For example, the financial information may
6
include a company's or group's payment of your
7
travel, lodging, or other expenses.
Likewise, FDA
8
encourages you at the beginning of your statement
9 to advise the committee if you do not have
any such
10
financial relationships.
11
If you choose not to address this issue of
12
financial relationship at the beginning of your
13
statement, it will not preclude you from speaking.
14
MR. CARROLL: Thank you, Mr.
Chairman, and
15
good afternoon to the committee.
My name is Kevin
16
Carroll, and I'm employed by AstraZeneca in the
17
role of global statistical leader for oncology,
18
based over in the U.K. What I'd
like to do for the
19
next ten minutes or so is to share with you some
20
thoughts and some data that I believe are relevant
21 to
your discussions with respect to the use of
22
progression as an endpoint in colorectal cancer
313
1
studies.
2
My time is limited, and I do hope you'll
3
forgive me if I rush through these slides a little.
4
In response to the workshop in November
5 and
the calls to look at progression and survival
6
data in the first-line setting, we at AstraZeneca
7 did
look at our experience in this area with
8
Tomudex, and we found that the data that we have in
9
that clinical trial and program support
10
progression-free survival in the first-line setting
11 as
a true surrogate for survival.
12
Furthermore, we undertook a brief review
13 of
the emerging mixture in this area and found that
14 the
observation made in our Tomudex program was
15
generally supported by the literature.
16
Furthermore, as we saw yesterday, there
17
were considerable concerns about using
18
progression-free survival in terms of issues
19
relating to the timing of the event and potential
20
introduction of bias. As we move
through these
21
next few slides, I hope to share with you an
22
alternative analysis being an event count analysis,
314
1
which I believe provides a simple alternative to
2 the
analysis of PFS time and avoids the kinds of
3
concerns that we have seen yesterday.
4
Lastly, we maintain that progression is a
5
meaningful endpoint in and of itself in first-line
6
colorectal cancer and, given the complexity of
7
crossover and the increasing number of available
8
effective therapies, should be employed as the
9
primary endpoint in the first-line setting, which
10 is
a view that is common with views expressed in
11 the
literature.
12
In the mid-1990s, AstraZeneca sponsored a
13
program of three Phase III randomized trials of
14
Tomudex versus 5FU in the first-line treatment of
15
advanced colorectal cancer. On
this next slide, I
16
briefly show you the results of these trials,
17
primarily to indicate that there is a treatment
18
effect on both progression-free survival and
19
overall survival in these trials.
And, therefore,
20 in
the same way as we've just seen, we can formally
21
assess whether there's any evidence of surrogacy in
22
this setting in this data set.
315
1
When we do that, we find
indeed that there
2 is
evidence based on these data that PFS is a true
3
surrogate for survival in this setting.
As has
4
been mentioned before and also a has been discussed
5 in
the committee in the past, progression is not a
6
matter of correlation--sorry, surrogacy is not a
7
matter of correlation. What we're
trying to
8
establish is whether the effect of treatment on the
9
endpoint of interest--in this case survival--is
10
mediated through an effect on an earlier endpoint.
11 In
simple terms, this means that if we were to do
12 an
analysis of survival and we adjusted for the
13
early effects of progression, would the treatment
14
effect on survival vanish? And, indeed,
if we do
15
that analysis on this data set, what we find is
16
that a survival analysis adjusting for
17
progression-free survival is no longer significant,
18 and
that suggests that progression is indeed a
19
surrogate, at least in this data set.
20
Furthermore, there are more sophisticated
21
means of assessing surrogacy, and I think we've
22
just seen some of those touched on.
And if we
316
1
apply these more up-to-date techniques, we're able
2 to
predict the effect of a 5FU-like treatment on
3
survival given its effect on progression. And I
4
think there's a mistake in your slides--in your
5
handout, and what we find in the Tomudex data is
6
that if progression was increased by, say, 50
7
percent, we would expect survival to be increased
8 by
around 29 percent, with a confidence interval as
9
shown. And I think such
predictions are going to
10 be
useful if we're thinking about using progression
11 in
the first-line setting.
12
The positive association between the
13
effect of treatment on survival and the effect of
14
treatment on progression-free survival is displayed
15 in
this figure, which is very similar to the one
16
that you've just seen. And this
is using the
17
methodology published by Buyse and Molenberg
18
recently.
19
What we see here, the circles are actually
20
regions in the trial program, in fact, distinct
21
countries that participated in the Tomudex trial
22
program. And what we see is there
is a significant
317
1
correlation between the effects of treatment on PFS
2 and
the effects on overall survival. And
that
3
further supports the surrogacy of progression-free
4
survival in this setting.
5
Of course, the little bit of data I've
6
shown you on Tomudex in response to comments made
7 in
the workshop is really only one small piece of
8
data, and I think we clearly have to look at all
9 the
available data in order to place this
10
information into context. And I
just placed on
11 this
slide the recently emerging and published
12
information in the first-line setting where I think
13 you
can see that there are large effects on
14
progression-free survival across a number of trials
15
which generally, but not always, are translating
16
into survival benefits. Clearly,
the
17
interpretation of these data is made complex by
18
crossover issues, by maturity issues, and follow-up
19
issues. But, nevertheless, I
think you might agree
20
that these data tend to support progression as an
21
endpoint in this setting.
22
Very similar to the previous presentation,
318
1
what we really need to do here is to apply a
2 meta-analytic
approach to all the available
3
first-line data in order to truly establish once
4 and
for all the relationship between progression
5 and
survival in this setting, and that would be
6
something that AstraZeneca would very much support
7 as
a willing participant.
8
Now, moving on briefly to talk a little
9 bit
about issues in using progression--and we saw a
10
number of issues debated yesterday, and this slide,
11 in
fact, was also used yesterday, where clearly
12
progression-free survival time is not known with
13
complete certainty, and that can lead to
14
overestimation and bias, and this is of great
15
concern.
16
The key question in my mind is:
What can
17 you
do about that? And I think there are a
number
18 of
very complicated, sophisticated ways of trying
19 to
deal with complicated sensory mechanisms and a
20
number of assumptions for the timing of event, and
21 I'm
not sure that any of those methodologies are
22
really satisfactory.
319
1
One simple approach that might be
2
considered, I think, is as an alternative, or at
3
least in support of PFS time analyses, that we
4
actually compare treatments on the basis of an
5
overall event count over the trial follow-up
6
period. This is an idea which is
actually very
7
similar to the single time point approach that I
8 think
was discussed both in the workshop in
9
November and also in the Advisory Committee in
10
December. And I'll show you a
quick example of
11
that in a moment.
12
Essentially, if you were to employ an
13
event count analysis, the benefit that you would
14
have is that you would be comparing treatments free
15
from concerns about the timing of the event, which
16 was
at least one of the issues yesterday.
The
17
treatment effect--the difference between treatments
18
could be described usefully in terms of the
19
relative risk of progression over the follow-up
20
period, and, furthermore, it's relatively
21
straightforward to show that if you use this
22
alternative endpoint, there's relatively little
320
1
loss in statistical power. And,
in fact, in
2
circumstances where the treatment effect is delayed
3 so
the Kaplan-Meier doesn't open at the beginning
4 but
opens at some later time point, it's actually
5
more powerful than the regular way we look at data
6
today. And, therefore, I would
think that this
7
kind of event count analysis should at least be
8
considered as a supportive analysis when looking at
9
analyses of progression-free survival time because
10 it
provides reassurance with respect to a lack of
11
bias and provides reassurance that perhaps
12
conclusions on PFS time are robust.
13
As I promised, I think it's helpful just
14 to
illustrate this endpoint with an example, and
15
this slide is rather complicated so I'll just take
16 a
moment to explain what's going on here.
17
What we can do is we could take a regular
18
Kaplan-Meier curve and we can break the follow-up
19
axis along the bottom as shown on this slide here.
20 The
blue circles on this slide represent the hazard
21
ratio derived from the regular analysis of PFS
22
time, and the red circle represents an analysis of
321
1 an
event count, ignoring the time to progression
2 and
getting around some of those problems we talked
3
about yesterday.
4
So if we consider the first three months
5 of
the Kaplan-Meier curve--sorry, the first six
6
weeks of the Kaplan-Meier curve, what we see is
7
that whether we do an analysis of PFS time in a
8
regular way or whether we do a simplified analysis
9 of
the events that occurred over that period of
10
time, you get essentially the same answer.
11
If we extend the follow-up period to a
12
12-week follow-up and then do a PFS time on the
13
first 12 weeks and get the hazard ratio--and we
14
plot that in blue--we can also calculate the
15
relative risk just on the numbers of events. And,
16
again, you can see that the two analyses are very
17
similar and so on through follow-up.
18
What this rather complex slide shows you
19 is
that there is really no difference between the
20
outcomes achieved when you use a PFS analysis and a
21
simplified event count analysis in this trial.
22
That suggests that the PFS conclusions reached
322
1
here, at least, are robust. There
is no bias
2
introduced because we see results that are
3
supported by a simpler analysis of event count.
4 And
I think, therefore, this provides some
5
reassurance that we can employ simpler methods of
6 the
data analysis and collection in first-line
7
colorectal trials and others when looking at PFS.
8
In summary, then, I would just close by
9 saying
that AstraZeneca's Phase III program data on
10
Tomudex provide evidence to support PFS as a true
11
surrogate for first-line colorectal cancer. The
12
recent literature I think is supportive of that
13
observation, that improvements in PFS are generally
14
followed by improvements in survival.
Furthermore,
15
there are always concerns using progression-free
16
survival, and I think we can consider an event
17
count analysis as at least as supportive analysis
18 if
not a direct replacement for the regular
19
analysis of PFS time when concerns exist about the
20
imputation of times and also asymmetric follow-up.
21
And, of course, an event count analysis can
22
accommodate and get around the issues of asymmetric
323
1
follow-up.
2
Finally, I would just say that,
3
irrespective of whether we ever formally and
4
convincingly establish surrogacy between PFS and
5
survival using rigorous statistical methodology in
6 the
first-line setting, we would maintain that
7
progression-free survival is a clinically
8
meaningful endpoint in and of itself.
And given
9 the
issues of crossover and an increasing number of
10
therapies available as second-line treatments, PFS
11
should be employed as a primary endpoint in
12
clinical trials in the first-line setting.
13
Thank you for your time and attention.
14
DR. KELSEN: Thank you, Mr.
Carroll.
15
We have time for one question.
Dr.
16
O'Connell?
17
DR. O'CONNELL: Yes, I just wanted
to make
18 a
comment that at the workshop the one point for
19
further research that emanated from that meeting
20 was
exactly what you just suggested to do.
In
21
fact, a formal meta-analysis from the cooperative
22
groups in the United States to determine the
324
1 association between progression-free
survival or
2
time to progression and overall survival to have a
3
more broad view than the two or three or now four
4
studies that have been discussed so far.
5
DR. KELSEN: Thank you, Dr.
O'Connell.
6
At this point, we're going to take a--do
7 you
have a question, Rick?
8
DR. PAZDUR: I have one. AstraZeneca did
9
three trials with--and I don't think you mentioned
10 the
results. What we're obviously interested
in
11
is: Does time to progression, if
you measure it,
12
predict for survival, subsequent survival? And of
13
those three trials that were using time to
14
progression, how did that correlate with survival
15 in
those individual studies? If you take--I
think
16 it
was like O11, O12, I forgot the actual numbers.
17 I
don't know the data specifically--
18
MR. CARROLL: Yes, I'm very happy
to talk
19 to
individual trial results. I think it's a
very
20
good question. I did flash up a
slide very
21
briefly, but time was short so I went straight past
22 it.
325
1
What we have, there were three trials,
2
each of about the same size, and what you find is
3
that in two of those trials you can individually
4
apply the formal Prentice criteria for surrogacy,
5 and
in two of those trials we see that about half
6 of
the effect on survival is explained by the
7
effect on progression-free survival, which is very
8
consistent with putting all the data together,
9
which is what I've shown on this slide.
10
So the individual trials support the
11
overall result in terms of surrogacy, and if we
12
apply--the other methodology that could be applied
13 is
the Buyse-Molenberg that we've seen before where
14 we
try and predict the effect on survival given the
15
effect on progression. And that methodology
can be
16
applied to two trials because one of the trials
17
showed a very small effect and, therefore, it was
18
kind of difficult to apply that methodology. But
19 in
the two trials where we could apply this
20
alternative methodology, again, we saw that there
21 was
a correlation, a significant correlation
22
between the effect on progression and effect on
326
1
survival. So the overall results
I've run through
2
quickly are supported by the individual trial data.
3
And, in fact, we will be publishing this material
4
with the--
5
DR. PAZDUR: So what you're
saying, if you
6
took all three of those trials, in two of them if
7 we
made a decision does PFS correlate with survival
8 and
improvement in survival, we would have been
9
correct in two of those trials.
There was an
10
improvement in PFS. And then
subsequently in that
11
trial, it was correlated with a positive effect on
12
survival. That was present in two
trials, and then
13 in
the third one it was not. Is that what
you're
14
saying?
15
MR. CARROLL: No. I'm saying that there's
16 one
trial where individually you can't apply--the
17
criteria we've talked about today require special
18
conditions to be in place for significant effects
19 and
endpoints. So you couldn't, strictly
speaking,
20
apply the criteria to some trials, so we don't
21
know. But the two trials we could
apply the
22
criteria, we could predict survival given the
327
1
progression effects.
2
DR. PAZDUR: Okay. Thank you.
3 DR. KELSEN: If there are no further
4
questions, we're going to take a ten-minute break.
5
We'll reconvene at 3:20.
6
[Recess.]
7
DR. KELSEN: Okay. Before we start, Dr.
8
Pazdur wants to make a few comments.
9
DR. PAZDUR: In my introductory
comments,
10 I
forgot to make a very important comment, and that
11
deals with the process that we're going through
12
looking at the endpoints. And I'd
like to express
13 the
agency's personal gratitude to both ASCO, the
14
American Society of Clinical Oncology, and AECR for
15
their efforts in assisting us with the various
16
workshops we've had. They've done
a terrific job.
17 The
people involved have been excellent in
18
coordinating multitudes of activities that go into
19
these workshops.
20
So, again, I wanted to bring that up, and
21 I
was remiss in not doing so. Thank you.
22
DR. KELSEN: Thank you, Dr.
Pazdur.
328
1
If we can turn to the questions of the
2
committee: In December, the
committee discussed
3 the
issue of disease-free survival as a general
4
matter dealing with many tumors.
And what the
5
agency would like us to talk about today is limited
6 to
colon cancer, not discussing other tumors.
7
I think everyone has had a chance to read
8 the
questions to the committee. I'd like to
go to
9
Question No. 1. I'll read
Question No. 1, and then
10
we'll open it for discussion.
11
Question 1: For colon cancer
drugs, could
12 an
increase in disease-free survival compared to
13
standard therapy represent clinical benefit and be
14 an
adequate basis for regular drug approval?
15
We'll open that now for discussion.
16
DR. PAZDUR: One point that I'd
like to
17
bring up is obviously we are assuming that there is
18 a
sufficient magnitude of effect, obviously if the
19
magnitude comes into being and is the data quality
20
appropriate, et cetera, assume that that's a given.
21 We
realize that that's a given.
22
DR. KELSEN: And assume that it's
either a
329
1
very large adequate trial or trials.
2
Discussion from the committee?
Dr.
3
George?
4
DR. GEORGE: I'll start. I think the
5
answer is yes, based on what I've heard and know,
6 but
it's what we know today with the current
7
therapies and the current modalities for detection
8 and
so forth, all those caveats. But that's
all we
9
have to go on. I think the future
may hold
10
something different, but so I'd say certainly the
11
answer is yes here.
12
DR. KELSEN: Dr. Brawley?
13
DR. BRAWLEY: I think the answer
is yes,
14 and
I'd actually also propose thinking about
15
something that would be a little perhaps
16
innovative. You could give a
tentative approval or
17
some type of approval based on disease-free
18
survival, and then that same cohort or the same
19
study population could ultimately be studied to get
20
overall survival later on.
21
During the period of time between the
22
initial approval for disease-free survival, you
330
1
could actually--people in the United States could
2
actually use this drug, and then there would be a
3
secondary review at the time the overall survival
4
data was available.
5
DR. KELSEN: Dr. George?
6
DR. GEORGE: I think, though, what
you're
7
talking about there sounds more like accelerated
8
approval. What this is talking
about is
9
disease-free survival as a clinical benefit itself,
10
which would be regular approval, unless you're
11
proposing to change--
12 DR. PAZDUR: Correct.
To follow up on
13
Otis' answer, basically, we normally would take a
14
look at mature survival data, with the caveat that
15
we're very interested, as Mike pointed out, that
16
there isn't any decrement in survival.
That's an
17
important point, and we've done this with multiple
18
applications outside of this area.
19
DR. KELSEN: Yes, Steve?
20
DR. GEORGE: I don't want to keep
jumping
21 in
here, but that's sort of Question 1(d), I think.
22
Could we--
331
1
DR. KELSEN: Yes, we'll get to--
2
DR. GEORGE: Do you want to wait
to come
3 to
that?
4
DR. KELSEN: What we're going to
do is
5
we're going to discuss and vote on the big print,
6 on
the big question of regular approval.
And then
7
depending on the vote of the committee, we'll then
8
look at the subcategories (a), (b), (c), and (d) as
9
they apply.
10
Ms. Roach?
11
MS. ROACH: My answer is yes, but,
as long
12 as
the novel treatments coming down the pike, the
13
work that's done--that's been done to show the
14
relationship is continued to keep showing that
15
relationship and the clarity of the relationship.
16
DR. KELSEN: Thank you.
17
Dr. O'Connell?
18
DR. O'CONNELL: Just to clarify
what Dr.
19
Pazdur said, a regular approval for three-year
20
disease-free survival would entail examination of
21 the
five-year survival to be certain that there
22
wasn't some delayed detriment, and that it wouldn't
332
1 be
necessary to look at simply accelerated approval
2 at
three years to assure that survival would be
3
subsequently examined. Is that
right?
4
DR. PAZDUR: We would negotiate
with the
5
sponsor to look at that. That
would be part of the
6
agreement.
7
DR. KEEGAN: Actually, I'm
concerned that
8 you
don't confuse a required committee to collect
9 the
data with an agreement. Regular approval
would
10 be
completed upon the three-year disease-free
11
survival data. So you may or may
not get the
12
five-year data. We would ask for
it, and it could
13 be
an agreed-upon commitment. But we
wouldn't have
14 the
same ability to withdraw an approval based on
15
failure to complete that commitment, for instance,
16
which may be a distinction without--
17
DR. BRAWLEY: Yes, I'm accepting
reality.
18 I
was at the beginning of my comment expressing
19
what I wish the law would allow.
I understand the
20 law
does not allow that.
21
DR. KELSEN: Dr. Williams?
22
DR. WILLIAMS: I'm hearing a
little bit of
333
1
confusion of comments. Dr.
Martino earlier
2
mentioned the concept that there might be
3
symptomatic recurrences and, therefore,
4
disease-free survival itself was a clinical
5
benefit, I would guess regardless of the time or
6 the
setting, et cetera, that delaying that
7
suffering was the endpoint. But
I'm also hearing
8
comments that, well, as long as things don't
9
change, et cetera, which would suggest that it
10
primarily is the surrogacy for survival that's
11
driving you.
12
So I don't know if you want to clarify
13
whether--that if you beat the best thing out there
14
with regard to disease-free survival in any realm
15 and
would that be clinical benefit, or would it
16
only be tied to this particular set of analyses
17
that have to do with surrogacy for survival?
18
DR. O'CONNELL: From my point of
view,
19
there would be clinical benefit associated with an
20
improvement in three-year disease-free survival per
21 se,
not as a surrogate. But I would also
want to
22
know what the long-term outcome is going to be to
334
1 be
certain there wasn't some unexpected deleterious
2
effect on overall survival.
3
DR. WILLIAMS: But you're not
requiring
4
that it fulfill the presumed surrogacy--
5
DR. O'CONNELL: Correct.
6
DR. WILLIAMS: --just that you
don't have
7 a
bad outcome.
8
DR. O'CONNELL: Correct.
9
DR. HIRSCHFELD: I'm sorry. A
10
clarification. I think the
question is
11
disease-free survival without a specific landmark
12
analysis attached to it, and it's not three-year
13
disease-free survival or some other prespecified--I
14
think that's--
15
DR. KELSEN: That is correct.
16
DR. HIRSCHFELD: --the point we're
seeking
17
advice on.
18
DR. KELSEN: Correct. That's number (a).
19
Dr. Rodriguez?
20
DR. RODRIGUEZ: I just had--I
guess it's
21 for
clarification. If indeed for whatever
reason
22
subsequently it was found that this combination or
335
1 this
drug did cause unexpected mortality, I assume
2 the
same process would follow through as is done
3
with, for example, the cardiac drugs that were
4
found to cause premature death?
5
DR. KELSEN: Dr. Pazdur?
6
DR. PAZDUR: For any approval,
yes, if
7
there is an unexpected toxicity associated, we
8
would review that, bring it back to this committee,
9 and
the drug could be withdrawn, that indication.
10
DR. KELSEN: Dr. Taylor?
11 [No response.]
12
DR. KELSEN: Other questions for
13
discussion?
14
[No response.]
15
DR. KELSEN: Okay. So I will read the
16
question again, and then we will vote on this
17
question. And I've been asked to
make sure
18
everybody pauses a little bit after the person
19
before them so they can get all the votes down
20
correctly.
21
So we're voting on the following question:
22 For
colon cancer drugs, could an increase in
336
1
disease-free survival--not yet defined--compared to
2
standard therapy represent clinical benefit and be
3 an
adequate basis for regular drug approval?
4
MS. ROACH: Yes.
5
DR. SARGENT: Yes.
6
DR. O'CONNELL: Yes.
7
DR. BRAWLEY: Yes.
8
DR. MARTINO: Yes.
9
DR. TAYLOR: Yes.
10
DR. REAMAN: Yes.
11 DR. REDMAN: Yes.
12
DR. KELSEN: Yes.
13
DR. CHESON: Yes.
14
DR. GEORGE: Yes.
15
MS. HAYLOCK: Yes.
16
DR. CARPENTER: Yes.
17
DR. RODRIGUEZ: Yes.
18
DR. DuBROW: Yes.
19
DR. KELSEN: That sounds unanimous
to me.
20
So the recommendation of the committee is
21
that disease-free survival be considered for
22
standard--as a clinical benefit for full approval.
337
1 And
now I'll ask for brief discussion and comment,
2 if
any, for 1(a), which for the audience asks the
3
question--guidance for the duration at which that
4
time point should be. Should that
time point be
5
three-year disease-free survival or five-year
6
disease-free survival or presumably some other
7
point in between?
8
DR. PAZDUR: And just to follow up
on
9
Grant's question so we are clear on this, what this
10
unanimous vote is saying is that you all feel that
11
this is of benefit in itself.
12
DR. KELSEN: Three-year versus
five-year.
13
Comments? Discussion? Dr. Carpenter?
14
DR. CARPENTER: I think everything
we've
15
heard rather careful and extensive study on is
16
three-year, and the lack of information,
17
well-documented information and careful study on
18 the
other endpoint, it would seem the most sensible
19 to use
the one that's been the best studied now and
20
leave it open to alternative durations.
21
DR. KELSEN: Dr. George?
22
DR. GEORGE: My comment on this is
that
338
1
three years, I think, seems reasonable as it exists
2
now, but it's a three-year minimum follow-up, I
3
think is what we're talking about, because the
4
accrual period could vary widely, and we're talking
5
about a minimum of three-year follow-up on each
6
subject, or at least enough follow-up on enough
7
patients for three years to have a reliable answer.
8
So I think there's some fuzziness here in
9
whether we want to be looking at three-year--a real
10
three-year disease-free survival or we just want
11
enough follow-up on all patients so we're
12
reasonably sure to have captured a--gotten a
13
reliable answer to the question we're trying to
14
ask, and that three years was based on primarily
15
because that's where the action was, so to speak,
16
that's where the events were occurring.
17
So I don't particularly--I'm not
18
particularly sold on the idea of looking at--say
19
when you end up looking at this one point in time,
20
three-year disease-free survival.
21
DR. KELSEN: Dr. Williams?
22
DR. WILLIAMS: Again, I think it
depends
339
1 on
what we're talking about. The reason
that you
2
would pick three years--certainly we've seen a lot
3 of
good comparisons to survival. But if you
take
4 the
philosophical attitude that it's benefit, it
5
would seem less important for that.
But, of
6
course, it is near the plateau and perhaps if you'd
7
like to get away from, you know, where most of the
8
action has occurred--I mean, do you have any
9
feelings regarding--out of the context of
10
surrogacy, why three years?
11
DR. GEORGE: You're asking
me? No, I
12
think as with any disease, you'd want to be sure
13
that you have gotten to a point where you're
14
reasonably sure that most of the events have
15
occurred. If you do it too early,
you're liable to
16
fool yourself. So you want to go
out far enough.
17
Now, that could change with time, with
18
therapies or improvements or such, but that's why I
19 say
I don't like sticking with the--I don't like
20
just saying three years versus five years. I think
21 it
should be more dependent on--I mean, if you
22
enter everybody--suppose you had a trial that
340
1
accrual was so rapid that everybody entered on the
2
first day. Then in three years,
you'll have most
3 of
the events. But if you have another
trial that
4
takes years to accrue, you're going to have those
5
early patients who will have some information, but
6 not
the later ones. And so you want to go
far
7
enough so you have enough information to make the
8
analysis an appropriate one.
9
DR. PAZDUR: I have a question for
Dan and
10 for
Mike, NSABP and NCCTG. When you're doing
an
11
adjuvant study, you're follow-up, your initial
12
analysis, your three-year analysis which you
13
normally do, would it be three years following the
14
last patient, or is it a median of three years
15
follow-up? Because, remember,
we're getting most
16 of
our data now on many of these adjuvant protocols
17
from the cooperative groups, and I need to know
18
their understanding on this point.
19
DR. SARGENT: I'll answer first,
Mike.
20
It's actually an event-driven analysis as opposed
21 to
a time-driven analysis. But our general
policy,
22
within NCCTG, at least, is to base our estimation
341
1 of
when that would occur based on a projected event
2
rate and accrual rate to project that analysis to
3
occur at about three years after the close of
4
enrollment. And so it's really
event-driven as
5
opposed to time-driven, and I'd just like to make
6
that point to emphasize what Dr. George indicated,
7
that I think it's very important to note that my
8
analysis that has been conducted did not just look
9 at
the single time point of three years. It
used
10 all
the data from the patients up until a time
11
point three years after the close of randomization.
12 It
used hazard ratio and logrank tests. It
did not
13
look at a specific rate at a specific time point.
T5A DR. O'CONNELL: The NSABP trials are also
14
15
event-driven, and so there are several interim
16
analyses and final analysis after a given
17
proportion or a certain number of events occur,
18
same as the NCCTG.
19
DR. KELSEN: Dr. Martino?
20
DR. MARTINO: I just want to
underscore
21 the
importance of these last few statements that
22
were made, because we've been throwing around this
342
1 three-year thing as if we all knew what it
meant,
2 and
there really are at least three possible things
3
that I understand it could mean.
I'm sure the
4
statisticians have more. And so
this becomes--you
5
know, understanding what we mean by this to me is
6
very crucial. You know,
recognizing that some of
7
these things are, in fact, driven by the
8
inter-group relationships, but there are drug
9
companies now who also run their own adjuvant
10
trials.
11
And so unless you have a clear
12
understanding, I could see me sitting here with
13
someone saying, yeah, but to us, three years
14
didn't--wasn't event-driven but, rather, was three
15
years from some date.
16
So we need to be very clear that we're
17
unanimous on this.
18
DR. KELSEN: I was actually going
to ask
19 if
you wanted to reformulate the question for us or
20
just leave it in this general sense back to you of
21
three-year disease-free survival.
22
DR. WILLIAMS: I think we
understand.
343
1
DR. KELSEN: Dr. Taylor?
2
DR. TAYLOR: I just wanted to say
what she
3 was
saying. It can't be just three years
from the
4
start. You have to make a
definition.
5
DR. KELSEN: Any other discussion?
6
DR. SARGENT: The data that I
presented is
7
three years minimum follow-up on each patient.
8
Now, having said that, this is an ongoing analysis,
9 and
we've started to look at three-year median
10
follow-up, and the initial results look very
11
promising with three-year median.
But a member of
12 the
audience during the break said, well, what
13
about two years? What about some
other time? And
14 so
I think that's still a question for ongoing
15
investigation, but the data that we've looked at so
16 far
does support the three-year minimum follow-up
17
time point and consider all data available up until
18
that time point.
19
DR. WILLIAMS: And I think you've
made a
20
good case that three years is when you're
21
approaching the plateau of the curve, and that
22 seems
like a reasonable basis. So we're
hearing
344
1
three-year minimum as your recommendation at this
2
point in time.
3
DR. KELSEN: Yes, do you need us
to vote
4 on this, or are you satisfied with the tenor
of the
5
discussion?
6
DR. PAZDUR: We're satisfied.
7
DR. KELSEN: Okay. If there's no further
8
discussion about that, (b) and (c) sort of are
9
answered since we voted in favor of regular
10
approval as representing clinical benefit. Would
11 the
agency like us to discuss (d) for guidance.
12
DR. PAZDUR: Yes.
13
DR. KELSEN: So I will briefly
read (d).
14 I
will summarize 1(d) for the panel.
15
Consider a study in which there is a
16
statistically significant difference in
17
disease-free survival, but after adequate follow-up
18
there's no evidence of a survival effect, there is
19 no
survival trend in favor of the experimental arm.
20
Would increased disease-free survival alone be
21
adequate for approval in this setting?
If so,
22
discuss the nature of the clinical benefit from the
345
1
increased disease-free survival when there's no
2
survival benefit. That is, the
study's presented
3 and
disease-free survival is clearly improved, but
4 you
look at the curves and it doesn't look like
5 survival is going anywhere.
6
Discussion? Dr. Martino?
7
DR. MARTINO: Well, I think we
actually
8
have discussed this, and I think the point that was
9
made originally was that we felt that in and of its
10 own
this would be a valuable clinical endpoint.
11 The
only caveat is if there had been a bad survival
12
outcome, in which case, you know, you have recourse
13 to
how you handle that. But it would
not--but
14
other than that, I think we've answered your
15
question. Haven't we?
16
DR. PAZDUR: I think you've
answered it,
17 but
what we're looking for is a little bit of
18
clarification why. Because there
are some of
19
perhaps a more conservative element that would say,
20 you
know, if you're just saying that you're sparing
21
people toxicity of chemotherapy for advanced
22
disease, or you're treating a far larger portion of
346
1
people with chemotherapy in the adjuvant setting.
2 So
why specifically in your clinical judgment do
3 you
think an improvement in disease-free survival
4 is
important?
5
DR. MARTINO: Well, what you all
have
6
reminded at least me of today is that when a person
7
recurs, you can sort of anticipate that within some
8
months--and those months aren't many--that, in
9
fact, they will be symptomatic.
And so for me,
10
that is good enough. I'm quite
satisfied that
11
preventing symptoms is valuable.
12
DR. KELSEN: Dr. George?
13
DR. GEORGE: To follow up on that
a little
14
bit, two points. One is the
clinical benefit is
15 in,
number one, that progression follows fairly
16
shortly; and, number two, there's something we
17
haven't discussed, I think, in that there's a
18
psychological aspect that I'm willing to sort of
19
accept, that if someone says if you delay
20
progression it's a good thing, sort of face
21
validity, almost, which I'm willing to accept that.
22 Of
course, I wouldn't be willing to accept it quite
347
1 as
readily if there weren't this knowledge that
2
there are symptoms coming soon after.
3
Now, here's the problem with the survival
4
thing, though, that I don't know--I think we have
5 to
really think this through. If you do
have
6
regular approval for disease-free survival and then
7
continue to follow for survival, there's at least a
8
theoretical possibility that some new agent would
9
have some weird mechanism of action that could have
10 a
nice effect on disease-free survival and have
11 some
longer-term deleterious effect on survival
12
through some mechanism that we don't know about.
13
Now, in a particular study if you were to
14
look at that, what might happen?
You might approve
15 it
based on disease-free survival, and you say,
16
well, as long--you gave the example of having, say,
17 no
effect on survival. But that implies, if
you
18 had
no effect on survival, that you're really not
19
ruling out an actual decrement in survival. I
20 mean,
you could actually have survival look better,
21 not
be significantly better. By usual
statistical
22
things, approaches, you would say, well, you really
348
1
haven't ruled out a slight negative effect. And if
2 you
had, say, the two survival curves lying flat on
3 top
of each other, you haven't ruled out probably a
4
pretty big decrement. This has to
do with the same
5
kinds of arguments that are made in non-inferiority
6
kinds of studies.
7
But that could put you in a quandary.
I
8
mean, you could say--especially it would put you in
9 a
quandary if survival starts looking a little
10
worse. I mean, it may not be worse,
but it's--you
11
really are worried that maybe what we've done here
12 is
approve something that looked good in
13
disease-free survival and, in fact, overall
14
survival could actually be worse, despite all our
15
work in looking at this as a clinical benefit in
16
itself and as a surrogate. So
that's a worry?
17
DR. PAZDUR: I realize you're
worried, and
18 we
would be looking at this, and I think most
19
sponsors would be following patients for survival.
20
Why? Well, obviously, if they
have a survival
21
benefit, they'd want to make that survival claim.
22
Now, the question that I have which we
349
1
asked for a first-line setting, but is really
2
germane here, if we moved away from survival as a
3
primary endpoint of a trial when we discuss these
4 to
a disease-free survival, what should the studies
5 be
powered for? Because that is a question. And,
6
remember, if we don't ask a survival question and
7
have under-powered trials, we have the potential of
8
never knowing that we have, you know, affected
9
survival, which would be very deleterious, I think,
10 to
the field of oncology in general, not to really
11
have an accurate depiction of what our therapies
12
really give patients.
13
We would be happy to have a primary
14
endpoint of disease-free survival and perhaps a
15
secondary endpoint where the trial would be
16
powered. Obviously, it would have
more patients, a
17
trial powered for survival. Am I
correct on that?
18
DR. SARGENT: Well, the event
rates for
19
disease-free survival after three years of
20
follow-up and for overall survival after five years
21 of
follow-up are virtually identical.
22
DR. PAZDUR: So they're not
different.
350
1
DR. SARGENT: So the power--the
sample
2
size should be the same.
3
Now, recognizing that if the trial follows
4 the
pattern of these, there is that slight
5
attenuation of the impact. And so
if the question
6 is
do we need adequate power to detect the slightly
7
attenuated effect, then you may need a somewhat
8
larger trial for overall survival, but not by very
9
much. We're talking about the
order of 10 percent,
10 and
the suggestion that I gave, I think, in
11
November was that if you did power it for
12
disease-free survival at, say, a hazard ratio of
13
1.4, you might consider powering it
14
for--overpowering it a little bit for, say, 1.35,
15
which would then give you the power to detect
16
overall survival at 1.4, assuming a slight
17
attenuation.
18
DR. PAZDUR: But we could, to
allay Dr.
19
George's fear, in the formal statistical analysis
20
plan require an analysis and data submission as
21
part of the move away from survival, looking at it
22 as
a secondary endpoint. And obviously you
would
351
1
have to win on overall survival as you--I mean, you
2
would have to win on disease-free survival to look
3 at
overall survival. But one would think
one would
4 do
that anyway, you know, the natural history of
5 the
disease.
6
DR. KELSEN: Dr. Williams?
7
DR. WILLIAMS: I think embedded in
this
8
question is the concern about what should you
9
expect to see with regard to the survival hazard at
10 the
time you do this minimum three years'
11
follow-up. And I don't know. Certainly things do
12
change over time, also, with treatments that may
13
have an effect on survival. So I
don't know if we
14
should be expecting to see a trend in survival, if
15
it's going to occur, at the time you would do this
16
analysis. Do you have any
idea? Should you be
17
expecting a trend in survival?
18
DR. SARGENT: At the three-year
time
19
point?
20
DR. WILLIAMS: Yes.
21
DR. SARGENT: I wouldn't count on
it. We
22
haven't looked at that issue specifically, but the
352
1
rate of death at follow-up time does not have that
2
sharp spike. People continue
actually to die at a
3
pretty uniform rate over the first five years, and
4 we
know that because we've tested the validity of
5
some of the statistical models.
For example, an
6
exponential survival model fits very well for
7
overall survival, which in essence assumes that
8
your risk of death each year is constant over time.
9 An
exponential survival model does not fit for
10
disease-free survival because there's this sharp
11
spike in recurrences earlier that falls off later.
12
So I think to answer the question, none of
13 the
data that we have analyzed would suggest that
14
there should be a clear, significant benefit for
15
overall survival at the three-year point just
16
because there is one in disease-free survival.
17
DR. WILLIAMS: And I wonder, do
some of
18 the
earlier studies that were using no treatment or
19
just surgery, might they have seen a little more of
20 an
early survival effect, you know, than the later
21
studies that include an active adjuvant arm--I
22
mean, the control as an adjuvant arm?
353
1
DR. SARGENT: I'm trying to make
sure I
2
understand the question. Could
you rephrase the
3
question?
4
DR. WILLIAMS: Well, would
you--when there
5 was
not an active adjuvant--active control arm,
6
would you have seen a survival effect earlier,
7
perhaps, you know, so you would have seen a
8
survival trend earlier than you would now where the
9 active control arm has an adjuvant active
control?
10
DR. SARGENT: It's actually been
pretty
11
consistent over time that if the curves separate,
12
they separate relatively early and continue with
13 the
separation, and that's been consistent both in
14 the
early trials and in the later trials that we've
15
looked at.
16
DR. KELSEN: Steve?
17
DR. HIRSCHFELD: In addition to a
18
decrement in survival, there's also interest in and
19 certainly
we have intentions to follow other events
20
which could be catastrophic, like second
21
malignancies, and these have shown up in some
22
circumstances or some delayed neurologic
354
1
impairment.
2
DR. KELSEN: Right, and with new
biologics
3 it
may be not five years, it may be seven years.
4 It
could be some other time.
5
Have you had enough discussion and
6
guidance from us and we don't need to vote on that?
7
DR. PAZDUR: Yes.
8
DR. KELSEN: Okay. So at this point we
9
have voted in favor of accepting disease-free
10
survival as representing clinical benefit and
11
approval, regular approval, and we'll move to the
12
next question, Question No. 2, which I'll read,
13
which now deals with advanced patients, presumably
14
Stage IV patients. When a
surrogate endpoint for
15
clinical benefit is needed in advanced colon
16
cancer, would the preferred surrogate endpoint be
17
progression-free survival or time to progression?
18
Discuss progression-free and TTP in the first-line
19
treatment setting first.
20
Discussion from the committee.
Dr.
21
Sargent?
22
DR. SARGENT: My point I guess
would be
355
1
that I don't think either TTP or PFS has been
2
validated as a surrogate endpoint in this setting.
3
DR. KELSEN: Other comments? Steve?
4
DR. GEORGE: We should probably
have a
5
clear-cut definition of a difference in these two
6
endpoints. I had a question about
this before.
7
DR. WILLIAMS: Primarily the
deaths are
8
included in progression-free survival.
9
DR. GEORGE: Right. That's the
10
difference, and the question--that makes the
11
question about the time to progression where you
12
could have deaths without progression.
There is
13
still a question of how those are handled. This is
14
sort of a technical point, maybe, but, you know,
15
it's a competing risk kind of problem.
16
DR. WILLIAMS: The point that Tom
Fleming
17 at
the workshop was that his belief was that the
18
clinical benefit endpoint should include deaths
19
because obviously it's a very important outcome.
20
Of course, there are those who believe
21
that the more pure tumor endpoint is time to
22
progression. If you're trying to
measure tumor
356
1
effect, that would be it. So, you
know, there are
2 two
different views on this.
3
DR. KELSEN: Dr. O'Connell?
4
DR. O'CONNELL: I guess I would
argue in
5
favor of including death in the parameter to be
6
assessed for a couple of reasons:
one, if a
7
patient dies and you don't have any information
8
about the cause of death, these patients all have
9
proven metastatic disease and there's a higher
10
likelihood that cancer contributed to that
11
patient's mortality in the advanced disease
12
setting.
13
And, secondly, if the patient dies because
14 of
toxicity related to the treatment, that's
15
awfully important to know from a clinical
16
standpoint.
17
DR. KELSEN: Dr. Redman?
18
DR. REDMAN: I tend to agree with
that. I
19
think including all deaths because sometimes we
20
don't know what the relationship is between the
21
treatment that we administer and a comorbid
22
condition that exists in this population.
357
1
DR. KELSEN: Can I ask the agency
to
2
comment on this? The question is
asking, if we
3
chose between these two alternatives as surrogates,
4 the
current regulatory stance is a survival
5
improvement. So is this question
asking--
6
DR. WILLIAMS: Those are, you
know, the
7
next questions. But as we go
forward in our next
8
questions, are they going to be PFS or TTP? Then
9 you
can answer the heavy questions.
10
DR. KELSEN: All right. Let's discuss the
11
light question first.
12
Dr. George?
13
DR. GEORGE: Well, I'll go back to
that
14
definitional issue, and I think it's the
15
progression-free survival that should be used for
16
reasons both because all these things we don't know
17
about the deaths that nominally don't occur with
18
recurrence, but also just from a technical point of
19
view, it gets more difficult to do those kinds of
20
analyses. They're not as
simple. And so I think
21 for
both those reasons I would prefer the
22
progression-free survival.
358
1
DR. KELSEN: Ms. Roach?
2
MS. ROACH: One of the things that
came up
3
very clearly in the discussion yesterday were the
4
problems with using either kind of progression
5
endpoint as a surrogate endpoint or a real
6
endpoint, such as how to deal with new lesions and
7
validating the progression of non-measurable
8
disease. How--can you formalize
that process?
9
DR. WILLIAMS: Yes. We definitely are
10
working on that, and we're going to be working on
11 the
guidance and have internal work on it, and
12
we're going to certainly have some external
13
discussion and comments. So we
certainly think it
14
needs a lot more work.
15
DR. PAZDUR: I'd like to amplify
that
16
point. I think that's an
excellent point, Nancy,
17
because that was, you know, a major problem with
18
some of the applications that we have seen.
19
I think oncology in general has relegated
20
this progression-free survival kind of to this
21
nebulous area where one doesn't address and
22
approach this with rigor. I think
we've outlined
359
1
some of the problems with it that will need to be
2 put
forward, not only in a guidance but in a plan,
3
prospective plan that the company writes, which may
4 be
different from one drug to another here.
I
5
think there's pros and cons of how to handle this.
6 But
it has to be prospectively managed--interval
7
between assessments, what to do if somebody misses
8 a
visit, how to handle the independent radiology
9
committee that is looking at this data versus what
10 the
investigator brings forward. One cannot,
after
11
somebody has taken a look at the data, decide,
12
well, I'll go with the investigator or I'll go with
13 the
independent review committee. Obviously
this
14
inflates error rates.
15
In colon cancer, we may want to look just
16 at
the radiology review since most people don't
17
have physical findings to that degree and in a
18
randomized study they'd balance out.
19
But this needs to have attention.
We're
20
talking internally about how to review the x-rays,
21 how
many of these x-rays to look at. We are
not,
22
obviously, going to look at 10,000 x-rays at the
360
1
FDA. We're going to be auditing
x-rays in that
2
regard.
3
The issue is one of--and I'm glad Dr.
4
DuBrow is here--including radiologists as
5
investigators, and I think that needs to be done
6
because it has to be--these reports that we get
7
have to have a uniform meaning to them.
We can't
8
just get these vague reports that the radiologists
9
give out--"There is a suggestion of a soft-tissue
10
mass. Clinical correlation is
indicated."
11
I think there's going to have to be
12
identification of a radiologist at each site,
13
adequate resources directed toward that individual,
14
measurements of the lesions prospectively by that
15
given radiologist.
16
DR. KELSEN: Dr. DuBrow?
17
DR. DuBROW: Can I just add one
thing?
18
That is, in your original conception of the
19
protocol that you've built into it radiographic
20
techniques that allow you to compare one study with
21
another so that the exact same technique is used
22
each time on the same type of scanner with the same
361
1
type of intravenous contrast, et cetera.
2
Otherwise, these studies become impossible to
3
compare.
4
DR. KELSEN: Dr. Taylor?
5
DR. TAYLOR: I'm going to have to
have a
6
very specific definition of what progression is
7
going to be because I think that can be very vague
8 as
well. It makes a study a much more
difficult
9
study for those of us who may be in Kansas and who
10
their patient comes in from Winfield to Kansas City
11
with their scans, and it's easier to always do it
12 in
Winfield. That's a big deal for some
patients,
13 and
you may end up scanning them that day
14
emergently, and you're comparing other scans. It
15
makes it more difficult in many ways for the
16
investigator.
17
DR. PAZDUR: To follow up
on--remember,
18
this criteria that we used were meant for response
19
criteria, not progression criteria, also, and so we
20
really need to revisit the whole area.
21
DR. TAYLOR: You have to define
that.
22
DR. KELSEN: Dr. Redman?
362
1
DR. REDMAN: I can't avoid a
political
2
statement. So you're in favor of
reinstituting the
3
funding budget to the cooperative groups up to the
4
level that was approved?
5
[Laughter.]
6
DR. PAZDUR: I love all cooperative
7
groups.
8
DR. KELSEN: Other discussion?
9
[No response.]
10
DR. KELSEN: Would you like us to
vote on
11
this point for you?
12
DR. PAZDUR: Yes.
13
DR. KELSEN: So I'm going to
phrase the
14
question as follows: When a
surrogate endpoint for
15
clinical benefit is needed in advanced colon
16
cancer, the preferred endpoint is progression-free
17
survival. Yes means yes, and no
would mean that
18 you
don't accept that.
19
MS. ROACH: Does yes mean yes with
all the
20
caveats we've put in there?
21
DR. KELSEN: Yes always means yes
with all
22 the
caveats.
363
1
MS. ROACH: Yes.
2
DR. SARGENT: Yes.
3
DR. O'CONNELL: Yes.
4
DR. BRAWLEY: Yes.
5
DR. MARTINO: Yes.
6
DR. TAYLOR: Yes, but I would like
to see
7 it
validated in some way.
8
DR. REAMAN: Yes.
9
DR. REDMAN: Yes for PFS.
10
DR. KELSEN: Yes.
11
DR. CHESON: Yes.
12
DR. GEORGE: Yes.
13
MS. HAYLOCK: Yes.
14 DR. CARPENTER: Yes.
15
DR. RODRIGUEZ: Yes.
16
DR. DuBROW: Yes.
17
DR. KELSEN: Two unanimous votes.
18
So we will now go to--we're now
19
recommending PFS as the surrogate, and now the
20
question--Dr. Pazdur?
21
DR. PAZDUR: Before we get into
Question
22 No.
3, I kind of want to lay out where our
364
1
discussions in the agency have gone, looking at
2
moving away from survival, because I think it's
3
important for people to realize that this has
4
undergone extensive discussion in the agency for
5
years. Okay? And we can't just look at this as,
6 you
know, one day we got up and we just think PFS
7 is
better than survival.
8
And when you're discussing these
9
questions--and I think this is particularly germane
10 in
colorectal carcinoma as we have more and more
11
agents available--the results of the oxaliplatin
12
first-line trial I think is a good example of
13
this--is the effect of--confounding effects of
14
therapies.
15
In essence, when we began our discussion
16 on
Monday, which many of you weren't here, we laid
17 out
some principles that one reason or several
18
reasons to move away from survival might be some
19
disadvantages. These would
include crossover or
20
confounding effects of other therapies, if there
21 was
a particularly long follow-up in the natural
22
history of the disease, for example, in indolent
365
1
lymphomas or carcinoids where it would be almost
2
impossible to look at survival data in a
3
meaningfully expedited fashion; and, thirdly, the
4
large numbers of patients that are frequently
5
required.
6
But we have to have a reason of why we're
7
moving away. It can't just be we
wake up one day
8
and, okay, we have a new committee here, the
9
committee five years ago or ten years ago voted on
10
survival, and now that there's new members here.
11
So I'd like to hear some discussion of why
12 in
this particular disease setting--and perhaps
13
I've already laid it out for you--is the reason.
14
DR. KELSEN: Okay. So we'll open that for
15
discussion. Dr. O'Connell?
16
DR. O'CONNELL: I think you did
lay out
17
the--
18
DR. PAZDUR: Not to lead you.
19
[Laughter.]
20
DR. O'CONNELL: Well, you don't
have to
21
lead very hard because that's exactly what I think.
22
It's interesting that the treatment of colorectal
366
1
cancer is migrating--is becoming much more similar
2 to
the treatment of breast cancer over the years.
3 And
many of the issues that we as GI oncologists
4
never had to face before, we're suddenly confronted
5
with. And with the multiple
alternative drugs that
6 are
now available, it makes it very difficult to
7 use
survival as a primary endpoint to evaluate the
8
initial treatment because of the effectiveness of
9 salvage therapy. I think that's the main reason to
10
consider progression-free survival as a valid
11
regulatory endpoint.
12
It's not so much to shrink the sample size
13 or
decrease the cost of doing clinical trials or
14
necessarily to make them more efficient.
It will
15
achieve all of those effects, but the real reason,
16 I
think, is that we now have to contend with--and
17
it's a very good thing to contend with--the
18
effectiveness of salvage therapy.
19
DR. KELSEN: Other comments from
the
20
committee? Dr. George?
21
DR. GEORGE: To follow up on that,
Mike,
22 are
you saying then that progression-free survival
367
1 is
a clinical benefit? Because I think we
don't
2
have the evidence for the surrogacy issue. But is
3 it
a clinical benefit in the same way just by
4
simply delaying progression that is somehow in
5
itself a benefit?
6
DR. O'CONNELL: It's a much more
7
controversial point, I think, than with
8
disease-free survival in the adjuvant situation,
9
because here these patients all have metastatic
10
disease, advanced, incurable malignant disease, by
11
definition in going into the study.
There's not
12 the
psychological benefit or psychological
13
detriment of realizing that you have a recurrence
14 in
the adjuvant situation. You know that
you have
15
incurable malignant disease as you go into these
16
treatments. So you don't have
that psychological
17
impact in the advanced disease setting.
18
And if one looks at a one- or two- or
19
three-month extension of progression-free survival
20 but
pays the price of a 25- or 50-percent rate of
21
grade 3 and 4 toxicity, how much clinical benefit
22 has
really accrued to the patient? And so
I'm less
368
1 convinced
that progression-free survival is of
2
clinical benefit in its own right.
I think that it
3 is
reasonably predictive of survival. I
don't
4
think that the data is nearly as robust for
5
progression-free survival as it is for disease-free
6
survival in the adjuvant situation.
But the
7
AstraZeneca data that we heard today, the two
8
trials that Dr. Miller presented, and a
9
meta-analysis that was referred to, all suggested
10
that progression-free survival did have some
11
correlation or surrogacy to overall survival.
12
Now, Dr. Sargent may have some additional
13
information that might tend to go a bit against
14
that argument, and perhaps he should share another
15
meta-analysis that I wasn't aware of.
16
DR. SARGENT: I think the data is
actually
17
relatively consistent on this point, and that is
18
that there is a moderate correlation between PFS or
19 TTP
and overall survival. The data that was
20
presented today had a proportion explained of about
21 50
percent. Previous analyses have also
shown
22
about a 50-percent proportion explained.
Some
369
1
relationship--I think it is actually pretty well
2
established that it's not a surrogate marker in
3
this case. I think further
analyses are probably
4
required, but there certainly, from my opinion, is
5 not
evidence of formal surrogacy in this case.
6
DR. PAZDUR: Could I make a point
or ask
7 you
a question? This was done from a
8
retrospective--a meta-analysis, I take it, your
9
statements?
10
DR. SARGENT: There is a
publication by
11
Burzykowski and colleagues in 2001, Journal of
12
Royal Statistical Society Series C, that actually
13 did
explore this exact point. It was a
limited
14
analysis, and they actually concluded that there is
15 no
evidence to support formal surrogacy of
16
disease--actually, I believe that was TTP and
17
overall survival. Not to say they
didn't consider
18
that there was a relationship.
There is a
19
relationship, there is a correlation, but it does
20 not
meet formal surrogacy criteria.
21
DR. PAZDUR: The issue that I
wanted to
22
bring up is if it was a meta-analysis done on
370
1
earlier trials, remember the magnitude of the
2
effect has a great deal to do with the relationship
3
between the surrogate endpoint and the eventual
4
outcome. If we took a look at
response rates, for
5
example, in colon cancer, the response rates in the
6 5FU
era were 15 percent, with 5FU-leucovorin, and
7 now
we're approaching 45, 50 percent in some
8
trials. Again, partial responses.
9
Would you take a look at--do you think
10
that that could have had some influence on it?
11
DR. SARGENT: Absolutely. I think you can
12
only--a surrogate is only as--can only be as strong
13 as
the effect is. And if there's a modest
effect,
14
then the surrogate can only do so much.
So I guess
15 my
point is that with respect to 5FU-based
16 treatments where the analyses have really
been
17
conducted, the multi-study analyses, they haven't
18
demonstrated it. It indeed become
stronger with
19
respect to the new regimens, but those analyses
20
just haven't been conducted at this time point.
21
DR. KELSEN: Ms. Roach?
22
MS. ROACH: I have a question for
Dr.
371
1
Hirschfeld or Dr. Keegan. Along
this line, as the
2
new--and I know I'm not supposed to talk about the
3
stuff coming down the pike, but there are some
4
things in the pipeline that seem fairly close to
5
coming to FDA for evaluation. And
they are much
6
less toxic, or at least that's my impression. And
7 one
of the things that--one of the issues that
8
comes up with treatment on a consistent basis is as
9
you're dealing with people who are progressing, you
10
don't want to put them in--I'm sorry.
It's been a
11
long day for everybody. You don't
want to expose
12
them to a toxic therapy, but if the therapy isn't
13
toxic, does that change the whole endpoint
14
discussion? Does that change the
framing of the
15
discussion?
16
DR. KEEGAN: I would say that for
some of
17 the
biologic products where there's been a
18
perception that they have a relatively modest
19
toxicity profile more in the range which is
20
observed with hormonal therapy, that that has been
21
taken into account in that the presumption is, as
22 for
many of the hormonal therapies, rightly or
372
1
wrongly, that there isn't really a lot of
2
treatment-related toxic deaths, which was part of
3 the
feeling behind the need to assess survival for
4 the
more toxic anti-neoplastic therapies.
5
I think my concern is that we started with
6 the
presumption that biologics might not be very
7
toxic, and I think what we're seeing is that what
8
they really have is a very different toxicity
9
profile. For instance, we don't
see traditional
10
cytopenias and alopecia, but we see other things.
11 And
that I think we don't have a lot of experience
12
weighing into whether or not that could ultimately
13
have a very negative effect both on, you know,
14
quality of life or even survival if they could do
15
that. I think that that's one of
the concerns.
16
I think the other is that I'm a little
17
leery of going--I understand what Dr. Sargent said
18
about the fact that we've got a lot of data with
19
anti-neoplastics and we don't have a lot of data
20
with the biologics yet to know if the same
21 predictability,
the same relationships are going to
22
hold.
373
1
So I think we're looking at two changing
2
fields at the same time, and it's a little hard to,
3 on
the one hand, say, well, I'm sure that all the
4
efficacy relationships will hold but the toxicity
5
issues won't really apply, they shouldn't come into
6
play here.
7
I would rather consider if we were going
8 to
treat them in a similar fashion, treat them kind
9 of
similar across the board, by and large, and not
10
make a presumption before we have the data that, in
11
fact, they might have the same kind of survival
12
impact or toxicity concerns that some of the more
13
traditional products--or at least not with as
14
little information as we have.
15
DR. HIRSCHFELD: I'd like to
respond also.
16 I
think the biggest driver in terms of the
17
attractiveness of the therapy is not the anticipated
18
toxicity, but it's the effect size.
And I
19
think with the evolution of small molecules as well
20 as
the biologics and immunotherapies, we will
21
always evaluate the toxicity versus the benefit in
22 making
decisions. And presumably the benefit
would
374
1
always outweigh whatever toxic events or adverse
2
events may occur. But what drives
the field
3
forward is the effect size, and there we will have
4 to
see as these data come in. And then we
can go
5
back to Dr. Sargent and ask him for a new analysis.
6
MS. ROACH: I have kind of a
follow-up on
7
that or just a comment real briefly.
I think this
8
discussion shows how complex this issue is, and I
9
think that transparency of process and product is
10
critically important to bring people along as we're
11
dealing with all of these different shifts in the
12
landscape. And I would urge FDA
to be more
13
forthcoming during reviews and approvals. For
14
example, posting the material, the briefing
15
material for ODAC is great. That
still leaves an
16
awful lot of products where that kind of material
17 isn't posted.
And I think that that's the kind of
18
thing that will help bring the community along and
19
help them understand why you all are choosing to do
20
what you do.
21
DR. HIRSCHFELD: All approved
products
22
have--just a point of information, all approved
375
1
products have the reviews posted now on the
2
Internet. The only reviews that
are not available
3
publicly are for those products which are not
4
approved at the time they're submitted.
5
DR. KELSEN: Dr. Taylor?
6
DR. TAYLOR: I want to go back to
the fact
7
that we haven't validated this.
I'm a little bit
8
uncomfortable in that I understand the problems
9
with survival and I'm very accepting that we don't
10
have good ways of determining these things. But
11
we've kind of thrown out response rate for various
12
reasons, partially because we don't think it
13 necessarily
correlates with survival, and now we're
14
going to be willing to accept what I would have
15
defined as stable disease on a number of Phase II
16
trials in that patients aren't progressing, they
17
have very stable disease. And I
think we do have
18 to
validate whether that truly means something.
19
I'm also less willing to say it is a
20
clinical benefit as I see a lot of people in the
21
palliative care setting who are not progressing but
22
have very miserable lives. And
you can have a very
376
1
stable disease and have lots of symptoms, and I'm
2 not
sure that it--I just really hope that we can
3
find a way to validate this or find some other
4
means.
5
DR. PAZDUR: Let me address that
issue.
6 You
know, when we're talking about stable disease,
7
we're usually talking about a single-arm trial.
8
Here we would be requiring a randomized study with
9 a
robust finding in this, and I think that's other
10
areas that we might want to discuss, how robust,
11 how
real that finding is.
12
Remember from my previous comments, we
13
have to first figure out if it's real, and then the
14
robustness of this and its relationship to toxicity
15
comes into play here, to get back to one of the
16
points Nancy was addressing.
17
The other issue that--you know, we are
18
fixated on this correlation between survival and
19
PFS, but remember, one of the other issues that has
20
been promulgated by the agency is not only is the
21
effect of a drug could be manifested by an
22
improvement in the quantity of life, but also in
377
1 the
quality of one's life. And I'm not
talking
2
about quality-of-life tools here.
I'm talking
3
about if people would consider this a relatively
4
established surrogate if one had an improvement in
5
progression-free survival or an improvement in
6
one's quality of life, perhaps even when they're in
7
that progression-free survival zone.
8
DR. TAYLOR: I think that's harder
to
9
define, though, and it certainly in a group is a
10
much harder thing to define, because as you work
11
with people and talk with them, there are some who
12 are
willing to trade coming to the doctor and
13
taking chemotherapy and others who are not. So I
14
think it's a much more difficult--I'm not sure it's
15
your perfect answer.
16
DR. WILLIAMS: I just want to make
the
17
observation, I think Dr. O'Connell suggested that
18 at
first recurrence, most patients are
19
asymptomatic; but then they subsequently progress
20 and
are symptomatic. So I would guess that
at
21
least in the first-line setting, most of those
22
stable disease patients would not be predominantly
378
1
symptomatic until they progressed again.
That I'm
2
just reading into your earlier comment, Dr.
3
O'Connell.
4
DR. TAYLOR: I think it depends on
when
5
they get to go on the study and when they decide
6 and
whether their doctor told them to wait until
7
they were symptomatic to take treatment.
8
DR. KELSEN: Dr. O'Connell?
9
DR. O'CONNELL: I wonder if I can
ask Dan
10 to
comment on the data that was presented at the
11
workshop where there were 1,000 patients treated
12
with irinotecan-based combination chemotherapy,
13
where there was a substantial difference in
14
treatment effect, about 50-percent objective
15
response rates with the irinotecan combination
16
treatments compared to the controls.
17
In those patients that received the
18
irinotecan-based treatments, time to tumor
19
progression--not progression-free survival in that
20 analysis
but time to tumor progression was highly
21
correlated with overall survival, even when
22
corrected for various prognostic discriminants
379
1
within a Cox covariate model.
It's not a formal
2
test of surrogacy, but does that data convince you
3 or
make you think that time to tumor progression
4
would be a reasonable predictor of survival?
5
DR. SARGENT: It's part of the
puzzle, but
6 two
trials looking at a single agent I don't think
7 are
sufficient evidence, at least to convince me.
8
DR. KELSEN: Other discussion from
the
9
committee?
10
[No response.]
11
DR. KELSEN: So a minute ago, if
we had to
12
choose a surrogate, we favored PFS.
But the
13
question we're being asked now is a different
14
question, so I'll read this again before we vote on
15 it.
16
For approval of drugs for first-line
17 therapy
of advanced colon cancer, presumably Stage
18 IV,
could PFS/TTP, understanding our previous
19
discussion, benefit of a new drug compared to a
20
standard first-line regimen comparitor on justify
21
regular or full drug approval?
And then the agency
22 has
got a small comment: Assume the standard
380
1
control arm has a known small survival benefit.
2
So we're now being asked to vote upon,
3 unless we have further discussion, the issue
of
4
whether we would recommend regular drug approval.
5 I
don't know whether we'll then discuss it would
6
have a role in accelerated approval or whatever.
7
Other discussion before we go to a vote?
8
[No response.]
9
DR. KELSEN: Okay. If not, Ms. Roach?
10
MS. ROACH: Can you start over
there this
11
time?
12
[Laughter.]
13
DR. KELSEN: Sure. Dr. DuBrow?
14
DR. DuBROW: Yes.
15
DR. RODRIGUEZ: Since I've gotten
less
16
convinced as I've heard later comments, I think my
17
answer is no.
18
DR. KELSEN: John?
19
DR. CARPENTER: I'm going to abstain
on
20
this. I'm not sure.
21
DR. KELSEN: Okay.
22
MS. HAYLOCK: Yes.
381
1
DR. GEORGE: No.
2
DR. CHESON: Yes.
3 DR. KELSEN: Yes.
4
DR. REDMAN: Yes, as long as we
get to the
5
answers of four.
6
DR. REAMAN: Yes.
7
DR. TAYLOR: No.
8
DR. BRAWLEY: Yes.
9
DR. O'CONNELL: Yes.
10
DR. SARGENT: No.
11
MS. ROACH: No, not until we have
all of
12 the
above.
13
DR. PAZDUR: A relatively mixed
vote, I
14
take it.
15
DR. KELSEN: It's an eight to five
vote.
16
DR. PAZDUR: Eight to five. Okay.
Let me
17
throw out this suggestion for you.
How about we're
18 in
a situation where we have a reason--we have an
19
improvement in progression-free survival or time to
20
progression, and the survival advantage is not
21
demonstrated; however, there is convincing evidence
22
that there has been crossover of therapies that
382
1
could explain why we're not seeing a survival
2 advantage.
Should we accept in that situation the
3
effect on the "surrogate" of time to progression?
4 And
this is a real live example of many years ago.
5
DR. KELSEN: Yes, it certainly
is. Open
6 for
discussion. There's a confounding
variable
7
that may have affected survival.
8
DR. PAZDUR: You can postulate a
reason
9 why
you have not demonstrated a survival effect,
10 for
example, confounding of the survival analysis
11 by
crossover.
12
DR. BRAWLEY: But, Rick, by the
same
13
token, a placebo would do the same thing.
14
DR. PAZDUR: No, I'm talking about
if you
15
have a known--you know, if you have, say, a
16
standard therapy or some--you know, not a
17
placebo-controlled trial we're talking about. I'm
18
talking about if you have a reason to deviate from
19
your suggestion here, would there--let me ask it in
20
another way. Is there any
situation where you
21
might deviate from this suggestion?
22
DR. SARGENT: I would deviate if
two
383
1
circumstances were present: A, we
have substantial
2
evidence of differential crossover; and, B, there
3 is
a trend in survival in the appropriate
4
direction. It may not be
significant, but at least
5
it's consistent with the PFS results.
6
DR. PAZDUR: Just to clarify, I
realize
7 you
answered the question in the affirmative.
For
8
those who felt negatively about it, okay? And
9
that's who I'm addressing this question to. Would
10
there be--
11
DR. KELSEN: I think it's
appropriate--
12
DR. PAZDUR: --sensitivity to not
being so
13
dogmatic as saying, no, I will only accept survival
14 in
those people.
15
DR. KELSEN: And this further
discussion
16 is
appropriate because, clearly, the magnitude of
17 the
vote indicated how big the unease is and how
18
controversial this point might be.
19
Is there any other discussion?
Yes, Dr.
20
George?
5B DR. GEORGE: I think my unease about it
21
22 was
because, unlike disease-free survival in the
384
1
adjuvant setting, progression-free survival I don't
2
think has been established in the same way as the
3
surrogate, nor is it obvious to me that it's the
4
same--has inherently something in it that's a
5
clinical benefit all by itself.
6
Now, with respect to the crossover issue,
7
I've made this point before, but no one seems to
8
listen, but I'll say it again just for a general
9
point. That is, I think this
falls into the
10
example of something where you would like to get
11 the
answer to something but you can't get it; that
12 is,
you say I have this new treatment and I'm going
13 to
compare it to the standard. I'd really
like to
14
know whether it prolongs survival, but I'm giving
15
this very early in the disease. I
have all these
16
other things that are liable to be given at some
17
point for some reasons that I can't control. And
18 all
I can do is I'm doing this randomized study,
19 and
I'll observe what happens.
20
My point about this is that is the answer;
21
that is, even--no matter what you try to do to try
22 to
explain it, the answer is if I start off trying
385
1 to
give these two treatments, in the current
2
setting with the available therapies and the
3
real-world situation, this therapy did not prolong
4 survival. Now, you can give reasons; it may be
5
because of crossover, may be because of other
6
therapies that were given. The
answer is still the
7
same. It didn't prolong survival.
8
So that's when you would definitely like
9 to
have something that could give you some answer
10
that, like progression-free survival might tell you
11
something biologically and say, all right,
12
something's going on here with this therapy. But
13 in
the real-world setting, it doesn't prolong the
14
survival. So that's the answer
with survival. So
15 if
I'm stuck with survival--
16
DR. PAZDUR: Would you buy, for
example,
17
progression-free survival in that situation, or in
18 any
situation, to reasonably likely predict
19
clinical--
20
DR. GEORGE: Yes, that's what I
was going
21 to
get to. I think that it's like an
accelerated
22
approval kind of thing. I don't
know if you may
386
1
want to talk about that.
2
DR. PAZDUR: Let me give you the
scenario
3
here so I think you people could understand the
4
real-world situation that we face frequently.
5
Obviously, people develop drugs and they are highly
6
touted to be very effective therapies, and there's
7
great interest on the part of patients to receive
8
these therapies before they are approved. Many
9
times we're requested both in the first-line
10
setting, and even more advanced disease setting,
11
that at the time of progression people will get a
12
perceived effective therapy even though it hasn't
13
been approved. And, therefore, we
can get into
14
problems when we have a survival analysis because,
15 you
know, both the groups of patients that are
16
randomized eventually will get the drug.
17
We saw that, for example, in the
18
third-line setting with oxaliplatin where the vast
19
majority of patients entered on the trial in the
20
third-line setting, I'm talking about, got the
21
drug. More, I think, for the more
advanced disease
22
setting, the later disease--
387
1
DR. KELSEN: Since this is now a
more
2
pressing issue, let me just look at Question 4, as
3 you
wrap it into your discussion, because now that
4
we've indicated by a split vote that PFS/TTP might
5 be
an acceptable standard for regular drug
6
approval, the agency wants to know a little bit
7
more, wants to know--does that mean they have to
8
have a big difference between these groups? Could
9 we
discuss the magnitude of that difference?
10 We frequently are talking about trial
and
11
trials, so could the committee comment on point 4?
12 Dr.
Redman?
13
DR. REDMAN: Yes, just for those
that
14
voted no, I mean, is it an absolute, or is it a
15
degree? If you have a randomized
trial, drug A
16
versus drug B, in a metastatic setting and the
17
progression-free survival of the standard is two
18 and
the progression-free survival is ten months,
19 and
yet it's going to take another three years to
20
find an overall survival advantage, is it an
21
absolute no, you won't accept that?
Or is it just
22 a
degree? Because I think that is what 4
is
388
1
asking. I mean, nobody's going to
say, gee,
2
there's a three-week progression-free survival, you
3
know.
4
DR. KELSEN: Well, I think the
agency is
5
asking that question. That's
exactly the question
6
that--
7
[Simultaneous conversation.]
8
DR. REDMAN: I think that's
dependent on
9 the
drug and its side effects, and I think that's
10
what clinical medicine is. You
can't make a cutoff
11 and
say, gee, you know, if it's one month, six
12 weeks, you know, if we're going to do bone
marrow
13
transplant, you're going to be in the hospital for
14
four weeks to get a four-week progression-free
15
survival, I mean--
16
DR. PAZDUR: --asking the question
because
17 I want to get some degree of flexibility here
on
18
where people stand, because people see these votes
19 and
obviously can come down and say, well, ODAC
20
said this; therefore, you must adhere to this. And
21 I'm
just wondering if we could have more discussion
22 on
people's flexibility on this point.
389
1
DR. KELSEN: So could we have
comments--
2
DR. PAZDUR: Maybe magnitude of
3 difference.
4
DR. KELSEN: Yes. Dr. Taylor, then Dr.
5
Cheson.
6
DR. TAYLOR: I think that, as
Bruce has
7
said, I think you have to individualize it. I
8
certainly wouldn't--I could be flexible if I saw a
9
dramatic difference between it.
But I think that
10 we
are choosing something that we haven't done
11
before, and we have to be very cautious.
And
12
certainly some of the drugs we looked at yesterday,
13
they would have had a--it had been on the market,
14 and
I don't think that would have been appropriate.
15
DR. KELSEN: Dr. Reaman and then
Dr.
16
Cheson.
17
DR. REAMAN: I would be flexible
also,
18
although I voted affirmative. But
I think in
19
general, the magnitude would have to be very
20
significant.
21
DR. PAZDUR: You're not talking
22
statistical significance.
390
1
DR. REAMAN: Clinically
significant, not
2
statistically.
3
DR. CHESON: I think it's not only
4
quantity but it's quality, and one of the
5
discussions yesterday we were talking about was
6
there some change in performance status, was there
7
some change in symptoms. And
there's a difference
8
between two months of good life and two months of,
9 as
Sarah was talking about before, really poor
10
quality of life. So I think you
have to be
11
flexible and individualize somewhat both on the
12
duration and what that duration means to the
13
patients. And for those sorts of
studies, you
14
should encourage them to obtain that other
15
information such as functionality--not necessarily
16
formal fact quality of life and those sorts of
17
things, although it's not a bad idea, but to get
18
other measurements that would support it.
19
DR. PAZDUR: One of the things as
we asked
20
in--perhaps--I don't know if you want to comment
21
about it, we would ask or we have been asking--in
22
discussing about this, asking for the trials to be
391
1
powered for survival, obviously, and to look at
2
that issue also.
3
DR. KELSEN: Dr. Carpenter?
4
DR. CARPENTER: It might be
helpful if we
5
just said that I think most of us would be looking
6 in
terms of months as opposed to days and weeks.
7
DR. O'CONNELL: Yes.
8
DR. CARPENTER: As far as an
increase, if
9 you
were to give an order of magnitude. Then
if
10
you're talking about months, the other things that
11
would be critically important would be the things
12
that Dr. Cheson mentioned.
13
DR. KELSEN: Dr. Reaman?
14
DR. REAMAN: I'm just going to
follow up
15 on
Dr. Cheson's comment, and, Rick, I think you
16
mentioned that you were going to be preparing a
17
guidance to industry, and I think it would be very
18
important to include as part of that the
19
suggestion, if not the requirement, to do formal
20
quality-of-life questions or to address those
21
issues.
22
DR. KELSEN: Ms. Roach?
392
1
MS. ROACH: My mom would love it
if I was
2 a
doctor.
3
I think the problem with black-and-white
4
answers on all this, while I understand you'd like
5 certainty, is that there's always a degree of
6
judgment. And so I think looking
at it in terms of
7
where we want to get and did we get there is maybe
8
more helpful. So the orders of
magnitude that you
9 all
are talking about are right by my perspective.
10
I also think that in terms of the
11
evidentiary requirements, there is a ton of really
12
interesting and intriguing imaging things coming
13
down the pike, with volumetric measures and
14
activity and things like that.
And I think if we
15
could use some of what we do here to validate the
16
technology as well as validate the drug, it would
17 be
helpful to everyone.
18
And I also want to put in a plug for
19
putting the funding back to the cooperative groups.
20
DR. KELSEN: So if I could
summarize, what
21 I
think we've heard is that the committee was for
22 and
has added guidance about it being but a
393
1
substantial difference in PFS/TTP, and the
2
magnitude of the evidence would be quite
3
convincing.
4
Do you want us to discuss 5 as well
5
or--okay. So I'll go to the last
point on the
6 agenda, which is: If one accepts PFS/TTP, what, if
7
any, survival evidence should be needed?
And the
8
agency specifically wants to know whether the
9
studies should be powered to rule out a negative
10
impact on survival and whether or not they should
11 be,
on the converse, powered to look for a
12
realistic improvement in survival.
So if one
13
accepted TTP or PFS. Dan, if you
want to make a
14
comment, or Steve?
15
DR. SARGENT: Well, my comment with
16
respect to 5(b) is a three-month improvement in TTP
17
that might translate into a three-month improvement
18 in
overall survival are very different elements.
19 And
requiring a trial, given the answer to No. 3
20 was
yes, requiring a trial to be powered for
21
overall survival may indeed be prohibitive given a
22
modest benefit that may be expected in overall
394
1
survival.
2
DR. WILLIAMS: I think this was
written
3
considering a very realistic setting, whereas the
4
competitor drug out there does have a survival
5
advantage of two years. And I
think, you know--two
6
months, I'm sorry. Right. So in that setting, I
7
mean, you have to think about would you or would
8 you
not be ruling out that you were inferior to the
9
other drug.
10
DR. SARGENT: I think 5(a) is very
11
reasonable. To rule out a
decrement is very
12
different than having power to demonstrate an
13
improvement. And so I think my
opinion on 5(a) is
14
yes; 5(b) is probably no.
15
DR. KELSEN: Dr. George?
16
DR. GEORGE: When I first saw
5(a), I
17
interpreted it a little differently.
I thought you
18
were looking at some non-inferiority trial which
19
would--I would have said no because it's huge. But
20 to
rule out a specific decrement, I think it's a
21
good idea to look for that to make sure that it's
22 not
done and to have that prespecified is a good
395
1
idea.
2
For (b), I'm a little less sure.
It
3
depends on the--you know, I guess the realistic
4
improvement, I don't know what that means exactly,
5
but--
6
DR. PAZDUR: Well, even now,
obviously,
7
when we ask for powers to be--the trials to be
8
powered, there is a guesstimation of an effect.
9 One
of the reasons why we are interested in this is
10
obviously we are facing increasing numbers of
11
single trials that are coming to us, and sometimes
12
trials that are underpowered, which leaves
13
everybody in a quagmire of what to do with these
14 trials. Do we have a real treatment effect? A
15
fear that if we go to a time to progression or
16
progression-free survival that would require a
17
fewer number of patients, we'll see a gradual
18
decrease in the size of patients numbers that are
19
being entered on trials.
20
Again, if we never ask a survival question
21 and
power for some type of survival improvement,
22
okay--and remember, we're asking for a robust
396
1
finding in time to progression which would probably
2
translate into a smaller survival effect. One
3
should be able to see that.
4
DR. GEORGE: What I was suggesting
in this
5
setting, it would be not necessarily to power to
6
detect realistic improvement, as you've stated it
7
here, but to design the study appropriately based
8 on
the time to progression and then look at--then
9
address the issue carefully of what that means,
10
what kind of things you could pick up with respect
11 to
survival, and when you could pick them up, and
12
make sure that--I mean, I'm just saying this in
13
sort of a subjective way. You'd
have to just
14
assess whether that seems reasonable, in other
15
words, not do it in the usual way you design a
16
study where you say I'm trying to pick up this kind
17 of
difference, but just say in this setting I can
18
pick up this sort of difference at this time during
19 the analysis.
You know, giving plots, in other
20
words, instead of just picking a point and saying I
21
have a specified power at this alternative.
22
DR. WILLIAMS: I have to say I
interpreted
397
1 the
question a little bit differently. I
actually
2
helped to write it. But to rule
out a survival
3
decrement, I mean, one interpretation could be
4
there's another drug out here with a two-month
5 benefit and maybe I'm being compared to
it. I want
6 to
make sure I haven't lost some of that.
So that
7
could be not very different from a non-inferiority
8
study; whereas, (b), you know, somebody can always
9
make some idea of how much survival you might be
10
detecting. So I'm not sure--do
you have any
11
guidance on (a) what we should be looking for?
12
We've got a little progression advantage, perhaps
13
substantial, compared to a drug that has a
14
two-month increase in survival.
Do we need in any
15 way
to rule out we're losing that, or we just
16
presume that we're not since we're--
17
DR. KELSEN: One of your problems
would be
18
because, as I think Mike said before--he had to
19
leave--with more and more new agents coming down
20 the
line, where are you going to see where you lost
21 the
survival? I mean, how will you do
that? And
22
that's what I was wondering, because you'll now
398
1
have a first-line therapy, a second-line. We're
2
talking about a third-line therapy.
You know, we
3
might get like breast cancer and have fourth-line
4 and
fifth-line therapies. And so where was
it lost
5 in
this off-protocol, presumably, list of agents
6
that the patient got? And I'm not
sure
7
procedurally how you'll be able to identify that
8
quite so easily, but I'd be interested in how it
9
statistically could be approached.
10
DR. GEORGE: This could be a real
problem
11 if
you're looking at it the way you just expressed,
12 as
some kind of non-inferiority. It would
be a
13
real problem in doing the studies.
And I think
14
that's not what you want to do because that's--you
15
know, they would be huge trials to answer--I mean,
16 to
not really address the really important
17
questions in this area.
18
So I think you have to do something kind
19 of
pragmatic, is what I'm thinking here, that you
20
would specify in the design something about what
21
you're going to be looking for.
But you don't
22
design the study to be definitively sure that
399
1
you're not more than some small decrement below the
2
control.
3
DR. WILLIAMS: So you're
suggesting some
4
kind of--basically a safety type decrement, in
5
other words, I can rule out that, you know, I've
6
induced some sort of survival decrement.
7
DR. KELSEN: I think one of the
problems,
8 you
know, in this, since we're talking about a
9
disease, in this disease, not like small-cell lung
10
cancer, for example, if the patients who enter the
11
first-line study are really almost asymptomatic or
12 to
a large amount asymptomatic, you have this
13
window. So it's not--if you don't
get them into
14
remission on the first regimen you won't have time
15 to
get to that second regimen. And so it
would be
16
really hard for you to look, I think, for that you
17
lost two months somewhere in there, but you'll have
18
hopefully more than one shot with currently
19
available therapy.
20 I'm sorry. Ms. Roach, you had a question?
21 Oh,
Dan?
22
DR. SARGENT: I think my proposal
would be
400
1
somewhat of a confidence interval-based approach
2
where we may not see an advantage for overall
3
survival, but we have a sufficient sample size to
4
estimate our confidence interval around our
5
estimated effect on overall survival that does
6
exclude a decrement in survival. So hopefully the
7
hazard ratio, you know, may not be significant, but
8 at
least is in the right direction and the
9
confidence interval is tight enough that we're sure
10
that it's not indeed a decrement.
11
DR. WILLIAMS: And I guess the
$100
12
question is: What is the size of
that decrement?
13
DR. SARGENT: I think it's
relevant to
14
what the improvement was compared to the previous
15
standard.
16
DR. KELSEN: Have we been able to
answer
17 the
questions that the agency posed? Are
there any
18
other questions that you'd like us to discuss or
19 any
other points you'd like us to discuss today?
20
DR. PAZDUR: We did have the
rectal cancer
21
question, and I don't know if that is something
22
people would entertain at this time, whether a
401
1
difference with rectal recurrence would signify
2
clinical benefit. And we're
talking about probably
3
adjuncts to radiation therapy, that type of a
4
situation.
5
DR. KELSEN: And just to refresh
people's
6
memory, when Dr. O'Connell gave his presentation,
7 you
might remember that he said the third point
8
from the workshop, in addition to what we've
9
covered today, was a recommendation that at
10
three-year disease-free survival--sorry, three-year
11
freedom from local failure in rectal cancer was a
12
very meritorious thing to have because of the
13
symptoms, and the agency I think is asking for
14
guidance and what's the view of the committee in
15
view of that.
16
DR. CARPENTER: That's regularly
17
associated with symptoms, and it seems to be--that
18
seems to be easier because clear delay or avoidance
19 of
major symptoms is just going to be a benefit, it
20
seems to me.
21
DR. KELSEN: Yes, the issue they'd
face
22 is,
you know, how you validate that they failed
402
1
locally but that's an imaging--doing careful
2
imaging question.
3
DR. CARPENTER: That's definable.
4
DR. KELSEN: Yes, that's
definable.
5
DR. CARPENTER: You could make
some
6
criteria of how you're going to do that.
7
DR. KELSEN: Is there any other
discussion
8
about that?
9
[No response.]
10
DR. KELSEN: Because we're making
a broad
11
recommendation in a few minutes.
But it sounds
12
like there's support for the workshop's conclusion
13
that this is an important issue for the agency to
14
consider as a different way of approving an agent.
15
Any other issues you would like
us to
16
discuss?
17
DR. PAZDUR: Not that I am aware
of. I'm
18
cognizant of the short discussion on this. We
19
would bring it back to the committee or for
20
external discussions with our consultants before
21
we'd make any final agreements regarding the latter
22
point, because I realize we haven't had sufficient
403
1
discussion on that. And plus many
of the members
2
have already left.
3
DR. KELSEN: If that's the case
and
4
there's no further discussion, I want to thank the
5
members of the committee for their participation
6
today, also for the opportunity to chair the
7 session.
Thank you very much.
8
[Whereupon, at 4:44 p.m., the meeting was
9
concluded.]
10 - - -