1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE
VOLUME II
Friday, March 4, 2005
8:00 a.m.
Gaithersberg Hilton
620 Perry Parkway
Gaithersburg, Maryland
2
PARTICIPANTS
Silvana Martino, D.O., Acting Chair
Johanna M. Clifford, M.S., RN, Executive
Secretary
COMMITTEE MEMBERS
Otis W. Brawley, M.D.
James H. Doroshow, M.D.
Antonio J. Grillo-Lopez, M.D., Industry
Representative
Pamela J. Haylock, RN, Consumer
Representative
Maha H.A. Hussain, M.D.
Alexandra M. Levine, M.D.
Joanne E. Mortimer, M.D.
Michael C. Perry, M.D.
Gregory H. Reaman, M.D.
Maria Rodriguez, M.D.
CONSULTANTS (VOTING)
Ralph D'Agostino, Ph.D.
Michael Proschan, Ph.D.
PATIENT REPRESENTATIVE (VOTING)
Sheila Ross - For Iressa
FDA
Martin Cohen, M.D. (a.m. session)
Grant Williams, M.D. (a.m. session)
Amna Ibrahim, M.D.
Nancy Scher, M.D.
Eric Colman, M.D.
Mark Avigan, M.D.
Richard Pazdur, M.D.
Robert Temple, M.D.
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C O N T E N T S
Page
Call to Order and Introductions
Silvana Martino, D.O. 5
Conflict of Interest Statement
Johanna Clifford, M.S., RN 7
Opening Remarks
Richard Pazdur, M.D. 10
Sponsor Presentation
AstraZeneca L.P.
Introduction and Regulatory History
Mark Scott, Ph.D. 15
Trial 709
Kevin Carroll, MSc 24
Clinical Actions and Implications
Judith Ochs, M.D. 37
Summary
Mark Scott, Ph.D. 56
Committee Questions 59
Open Public Hearing 89
Committee Discussion 107
- - -
Call to Order and Introductions
Silvana Martino, D.O. 140
Conflict of Interest Statement
Johanna Clifford, M.S., RN 142
Opening Remarks
Richard Pazdur, M.D. 145
4
C O N T E N T S
(Continued)
Page
FDA Presentation
Regulatory History of Zometa and Aredia
Nancy Scher, M.D. 147
Post-Marketing Safety Assessment of
Osteonecrosis of the Jaw: Pamidronate
and Zoledronic Acid
Carol Palmer, R.Ph. 155
Osteonecrosis of the Jaws in Myeloma:
Time Dependent Correlation with Zometa
and Zometa use
Brian Durie, M.D. 173
Sponsor Presentation
Novartis
Pharmaceuticals
ONJ Reported in Bisphosphonates Treated
Patients - An Overview
Diane Young, M.D. 188
Clinical Benefit of Bisphosphonates in
Cancer
Patients with Metastatic Bone Disease
James Berenson, M.D. 222
Open Public Hearing 229
Committee Discussion 252
5
P R O C E E D I N G S
Call to Order and
Introductions
DR. MARTINO: Good morning, ladies and
gentlemen.
The topic before us this
morning is some
additional new data that has arisen
relative to the
agent Iressa. Before we start with the topic
itself, I am going to ask the committee
to
introduce itself, and we will start on my
left with
Dr. Pazdur, please.
DR. PAZDUR: Richard Pazdur, FDA.
DR. WILLIAMS: Grant Williams, FDA.
DR. COHEN: Martin Cohen, FDA.
MRS. ROSS: Sheila Ross, Lung Cancer
Alliance formerly ALCASE.
MS. HAYLOCK: Pam Haylock, Oncology Nurse,
University of Texas Medical Branch in
Galveston.
DR. LEVINE: Alexandra Levine, University
of Southern California, Chief of Heme.
DR. RODRIGUEZ: Maria Rodriguez, M.D.
Anderson Cancer Center.
DR. REAMAN: Gregory Reaman, Pediatric
6
Oncologist, Children's Hospital,
Washington, D.C.
DR. MARTINO: Silvana Martino, Medical
Oncology, Cancer Institute Medical Group
in Santa
Monica.
MS. CLIFFORD: Johanna Clifford, Executive
Secretary to the Oncologic Drugs Advisory
Committee.
DR. HUSSAIN: Maha Hussain, Medical
Oncology, University of Michigan.
DR. PERRY: Michael Perry, Medical
Oncology, University of Missouri, Ellis
Fischel
Cancer Center.
DR. MORTIMER: Joanne Mortimer, Medical
Oncology, University of California at San
Diego.
DR. GRILLO-LOPEZ: Antonio Grillo-Lopez.
I am a hematologist/oncologist, a
five-year cancer
survivor, and I am here as the industry
representative on this committee. I would like to
state that although I am the industry
representative, I receive no support
whatsoever
from industry for my presence here.
DR. PROSCHAN: Mike Proschan. I am from
7
the National Heart, Lung, and Blood
Institute.
DR. D'AGOSTINO: Ralph D'Agostino, Boston
University, Biostatistician.
DR. BRAWLEY: Otis Brawley, Medical
Oncology and Epidemiology, Emory
University.
DR. DOROSHOW: Jim Doroshow, National
Cancer Institute.
DR. MARTINO: Thank you.
Next, I would like Ms. Clifford
to read
the Conflict of Interest Statement for
the group.
Conflict of Interest
Statement
MS. CLIFFORD: The following announcement
addresses the issue of conflict of
interest and is
made a part of the record to preclude
even the
appearance of such at this meeting.
Based on the submitted agenda
and all
financial interests reported by the
committee
participants, it has been determined that
all
interests in firms regulated by the
Center for Drug
Evaluation and Research present no
potential for an
appearance of a conflict of interest with
the
following exceptions:
In accordance with 18 U.S.C.
208(b)(3),
full waivers have been granted to the
following
participants. Please note that the
following
8
consulting activities waived are
unrelated to
Iressa and its competing products.
Dr. Silvana Martino for
consulting for a
competitor, which her employer receives
less than
10,001 per year.
Dr. Michael Perry for
consulting with a
competitor which he receives less than
10,001 per
year.
In addition, Dr. Perry has been granted a
waiver under 21 U.S.C. 505(n) for owning
stock in a
competitor, valued between $5,001 to
$25,000.
Because his stock interest falls below
the de
minimis exception allowed under 5
CFR(b)(2), a
waiver under 18 U.S.C. 208 is not
required.
Dr. Maha Hussain has been
granted waivers
under 208(b)(3) and 21 U.S.C. 505(n) for
owning
stock in a sponsor and a competitor. These stocks
are valued from 25,000 to 50,000 per
firm.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
9
Agency's Freedom of Information Office,
Room 12A-30
of the Parklawn Building.
With respect to the FDA's
invited industry
representative, we would like to disclose
that Dr.
Antonio Grillo-Lopez is participating in
this
meeting as an acting industry
representative acting
on behalf of regulated industry. Dr. Grillo-Lopez
is employed by Neoplastic and Autoimmune
Disease
Research.
In the event that the
discussions involve
any other products or firms not related
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement,
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any firm whose products they may wish to
comment
upon.
DR. MARTINO: Thank you.
Next on our agenda is Dr.
Richard Pazdur,
10
who will address the committee and give
us some
direction for this morning's meeting,
please.
Opening Remarks
DR. PAZDUR: Thank you, Dr. Martino.
Iressa was originally approved
by the FDA
on May 5th, 2003, as a monotherapy for
the
treatment of patients with locally
advanced or
metastatic non-small cell lung cancer
after failure
of both platinum-based and docetaxel
chemotherapies.
Partial tumor responses
occurred in
approximately 10 percent of
patients. Iressa was
approved under the accelerated approval
regulations. As discussed yesterday, these
regulations allow approval based on a
surrogate
endpoint reasonably likely to predict
clinical
benefit and require subsequent studies to
verify
and define its clinical benefit.
As an approval condition, AstraZeneca
committed to conduct a randomized trial
examining
the Iressa effect on survival in patients
with
advanced non-small cell lung cancer who
had
11
received 1 to 2 prior
chemotherapies. This is
defined as Trial 0709.
The primary endpoint of this
trial was
overall survival and improved survival
for
Iressa-treated patients was to satisfy the
requirement for the demonstration of
clinical
benefit.
For drugs approved under accelerated
approval, the FDA may withdraw approval
for the
failure of a post-marketing study to
verify
clinical benefit. I should note that there were
several studies that were included in
their Phase
IV commitment.
The withdrawal procedure
requires a formal
hearing whose composition and procedures
are
defined in the Code of Federal
Regulations. This
meeting is not that formal hearing.
AstraZeneca notified the United
States
Food and Drug Administration on December
17th,
2004, that a large randomized study
comparing
Iressa plus best supportive care to
placebo plus
best supportive care failed to
demonstrate a
survival advantage for Iressa in the
treatment of
12
non-small cell lung cancer.
The results will be reported in
detail by
AstraZeneca during this meeting.
The FDA has not received the
complete data
set for this trial, especially data that
would
allow pharmacogenetic or
immunohistochemistry
subset analysis. The FDA management plan is rapid
communication of the above trial results
to health
care professionals and patients
concurrent with the
expeditious completion of the trial
analysis by
AstraZeneca, including the effects of
EGFR status
determined by immunohistochemistry and
EGFR
mutational status on survival.
We are interested in reviewing
the
immunohistochemistry subset analysis
since
interesting exploratory findings were
included in
the Tarceva label that was recently
approved this
year.
The FDA will not make a
regulatory
decision on Iressa until the data
regarding subset
analysis and the study results are
received and
reviewed.
In the interim, AstraZeneca has
13
suspended promotion of Iressa, but will
continue to
make the drug available to patients who
appear to
be benefiting from Iressa treatment.
Actions have been taken to
communicate the
most recent Iressa information to health
care
professionals and patients.
These are delineated in the
preamble to
the discussion points and include: AstraZeneca
press release of the ISEL study results,
Dear
Doctor letters notifying physicians of
the study
results and alternative therapies
available,
AstraZeneca sales force distribution of
Dear Doctor
letters, other Dear Doctor letters being
posted on
the AstraZeneca website, patient advocate
groups
being notified, AstraZeneca
communications to known
patients, information being posted on the
FDA
website, abstracts at meetings, journal
placements
of the Dear Doctor letters,
advertisements on a
continuing basis in all issues of the 10
most
widely read oncology journals urging
physicians to
consider options other than Iressa.
A copy of this advertisement is
attached
14
in today's Discussion Points.
AstraZeneca is also tracking
total and new
Iressa prescriptions every two weeks to
ensure that
the above communications are resulting in
decreased
Iressa use.
We are not here today to vote
on the
ultimate regulatory fate of this
drug. We may be
bringing this question back to future
ODAC meetings
after the FDA reviews this study and
additional
subset analysis.
The purpose of this ODAC
meeting is to
provide transparency of the process that
we have
undertaken and to obtain your input on
the adequacy
of these steps to date to ensure that
patients and
prescribing physicians are aware of the
study
results and treatment options other than
Iressa
while allowing the drug to be available
to patients
who may be benefiting from it.
Thank you.
DR. MARTINO: Thank you, Dr. Pazdur.
A new member has joined
us. Dr. Temple,
if you would be so kind as to introduce
yourself.
DR. TEMPLE: Good morning.
Bob Temple,
Office Director.
DR. MARTINO: Thank you.
For the
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audience, as well as the committee, I
want to
remind everyone that this morning's
purpose is not
to decide the fate of this drug, so those
of you
who are here thinking that that is what
we are
going to do, please relax, that is not
the point.
The point this morning is
realizing that
there is some new information that needs
to be
properly disseminated to the public, both
the
medical public as well as the lay public,
has that
process taken place and what is that
process.
So, those really are the issues
before
this committee.
At this point, I would like AstraZeneca to
approach the podium and introduce your
speakers, as
well as give us some understanding of
what they
will be speaking on please.
Sponsor Presentation -
AstraZeneca L.P.
Introduction and Regulatory
History
DR. SCOTT: Thank you, Dr. Martino.
My name is Mark Scott and I am
the U.S.
Development Leader for Iressa.
As Dr. Pazdur just mentioned,
Iressa was
granted an accelerated approval under
Subpart H in
May of 2003 to treat advanced non-small
cell lung
cancer after failure of two types of
chemotherapy.
16
Subsequent to Iressa's approval, this
committee has discussed in general the
terms of the
Subpart H approval guidelines and the
need for
rapid completion by sponsors of their
post-marketing trials that are required
as part of
such an approval.
During these discussions, an
important
question was raised by ODAC, what should
be done if
a confirmatory trial does not meet its
primary
objective. The ODAC discussion at the time
acknowledged that there would probably be
no quick
and easy answer if this situation were to
arise.
We are here today because this
hypothetical situation is now real and it
applies
to Iressa. The study we are here to discuss is
Trial 709, one of the confirmatory trials
for
17
Iressa which did not achieve statistical
significance for its primary endpoint of
overall
survival.
We will describe for you the actions
AstraZeneca has undertaken to communicate
the
results of Trial 709 to physicians, so
that
informed decisions can be made regarding
the
clinical use of Iressa.
Today, we will describe
important findings
from Trial 709, how the data from Trial
709 is
actually quite similar to prior clinical
data on
Iressa and additional analyses, and
clinical trials
that are being conducted or planned to
better
understand which patients are most likely
to
benefit from Iressa.
We will also outline the
timings of
availability for data for FDA review,
what has
occurred and the future direction for
Iressa,
provide important lessons about drug
development,
and accelerated approval in the era of
targeted
oncology therapies.
After I cover a brief
regulatory history,
18
Mr. Kevin Carroll will speak more on
Trial 709,
then, Dr. Judy Ochs will present the
actions
AstraZeneca has taken to inform the
oncology
community and the implications for the
development
of Iressa. I will then review the timelines that
we have to provide data to FDA.
As posed to the committee by
FDA, we look
forward to hearing the Committee's
thoughts on the
appropriateness of the communications
taken
regarding Trial 709.
Today, we have two experts on
lung cancer,
Howard Burris from Sarah Cannon and Mark
Kris from
Memorial Sloan- Kettering, and they will
be
supporting the AstraZeneca staff here to
answer any
questions the Committee may have.
Lung cancer is the most common
cancer and
the leading cause of cancer mortality in
both men
and women with over 170,000 new patients
being seen
each year in the United States.
The disease is complex, most
patients are
diagnosed with advanced disease, symptoms
are
common, and the prognosis is poor.
Standard first line therapy for
advanced
disease was, and continues to be,
platinum-based
doublet chemotherapy. Prior to 2003, after failure
19
of first line therapy, only docetaxel had
been
demonstrated to improve overall
survival. No
therapy had been approved for use after
failure of
both first and second line therapy.
Standard chemotherapies do
offer benefits,
but with significant toxicity. Therefore, there
are many lung cancer patients who cannot
tolerate
any chemotherapy.
There was a great demand for
new, active,
less toxic agents for non-small cell lung
cancer.
Now, Iressa is a small molecule inhibitor
of the
epidermal growth factor inhibitor
tyrosine kinase.
EGFR expression plays a role in
angiogenesis,
apoptosis, proliferation in many
tumors. Iressa is
thought to mitigate against these
factors.
The Iressa Phase I program
began in 1998
and doses up to 1,000 mg/day were
studied. Among
the 289 subjects enrolled, the most
common
toxicities were low-grade diarrhea and
rash, and
20
the dose-limiting toxicity was reversible
Grade 3
diarrhea, and this dose-limiting toxicity
occurred
at doses beyond 800 mg/day.
Marked anti-tumor activity was
seen in
non-small cell lung cancer population
that
participated in the Phase I program, and
there were
actually 10 of 100 patients where
responses were
noted, and these responses occurred
across the dose
range.
Because of the safety findings
and the
activity findings in Phase I, we chose
the doses of
250 and 500 mg/day to be further
investigated in
the third line monotherapy setting, as
well as in
first line trials in combination with
platinum-based chemotherapy.
I will now focus on the data
relevant to
the accelerated approval of Iressa.
IDEAL I and II were trials
conducted among
patients where chemotherapy had
failed. Both
trials randomized patients between 250 mg
and 500
mg of Iressa per day. The primary endpoint in each
trial was objective response, the
requirement for
21
response was at least a 50 percent
reduction in
measurable tumor area, or significant
reduction in
non-measurable disease, and these
decreases needed
to persist for at least one month.
Across doses, response rates
seen in IDEAL
I and IDEAL II were 19 and 10.6
percent. Responses
were durable with ranges of 13 months and
7 months
for IDEAL I and II respectively.
Also of note was the
variability that was
seen in response across some
subgroups. Higher
rates were seen in females, never
smokers, those
with adenocarcinoma histology, and of
those of
Asian ethnicity.
As you will see in a few
minutes, this
same variability in response is suggested
for
survival, as well, when Trial 709 was
further
analyzed.
There were no differences in efficacy
between the two doses, and the survival
curves are
presented on this slide where we have
collapsed
IDEAL I and II together and looked at 250
versus
500, and the survival curves were
completely
overlapping.
As for safety, the most
drug-related
adverse events were of low grade, while
the most
common adverse events were rash and
diarrhea.
22
There were a greater number of events at
the 500 mg
dose.
On the basis of these data, the 250 mg dose
was chosen on the basis of its efficacy
and
tolerability as part of our application
for
accelerated approval as a monotherapy in
refractory
disease.
As Dr. Pazdur mentioned, Iressa
was the
subject of the ODAC in September of
2002. These
response rate and safety data were
reviewed, and
the committee voted in favor of
accelerated
approval.
The FDA granted accelerated
approval in
May of 2003 in patients refractory to
both
docetaxel and a platinum-containing
regimen. The
post-approval commitment trial started in
July of
2003.
We agreed to conduct and
analyze and
report on three additional clinical trials, to
examine the effects of Iressa as a
monotherapy in
23
patient with advanced non-small cell lung
cancer
where chemotherapy had failed.
These included Trial 709 where
an
improvement in survival was sought, and
the
preliminary results will be the focus of
Mr.
Carroll's presentation today.
Trial 721 examines whether the
survival
seen with Iressa is not inferior to
survival seen
with docetaxel. There is a planned interim
analysis of this trial with complete data
for this
to be available in June of this year, and
with
survival data from this trial available
in November
of next year. The results from this trial can
confirm the effectiveness of Iressa.
Trial 710, the third Subpart H
commitment,
was a placebo-controlled trial where an
improvement
in symptoms was sought. However, the early
availability of results from Trial 709 in
December
of last year compromised the ability to
recruit
patients.
As a consequence, the
independent Data
Safety Monitoring Committee recommended
that
24
further recruitment was not justified
because the
trial was unlikely to be completed. In agreement
with FDA, this trial was stopped in
September of
last year.
Two other trials featured as
additional
commitments that were not linked to the
accelerated
approval, we were asked to provide
reports on the
SWOG 0023 and BR19 trials.
These placebo-controlled trials
seek to
demonstrate a survival improvement for
Iressa after
definitive therapy in two settings of
non-small
cell lung cancer. Both trials continue to recruit.
In summary, there were three
Subpart H
confirmatory trials and two additional
trials. One
has been closed, three are ongoing, and I
will like
to ask Mr. Kevin Carroll, the
statistician for
Iressa, to come and share with you the
fifth trial,
Trial 709.
Trial 709
MR. CARROLL: Thank you, Mark.
Today, I will be presenting to
you
preliminary data from Trial 709, which is
a large
25
randomized Phase III trial comparing
Iressa to
placebo in advanced chemotherapy-failed
non-small
cell lung cancer.
The data I will be sharing with
you today
are as we saw them for the first time on
December
16, 2004, and so are consistent with the
materials
in your briefing document.
Since then, the data have been
further
validated, in fact, were finalized on the
2nd of
February 2005. There have been few changes to
these data and none that materially
affect the
results I will be showing you today.
In Trial 709, 1,692 patients
were
randomized to Iressa or placebo on a 2 to
1 basis
in 210 centers across 28 countries. In light of
the approval of Iressa in the U.S.A. in
May 2003,
no U.S. sites were included in this
trial, as
randomization to placebo was considered
infeasible.
Further, to ensure balance
between the
treatments at baseline, the randomization
was
stratified for histology, gender, reason
for
failure to prior chemotherapy, and
smoking history.
In terms of key eligibility
criteria, the
patients randomized into Trial 709 had
advanced
non-small cell lung cancer and had failed
1 to 2
26
prior chemotherapy regimens.
Furthermore, the patient
population
entered into Trial 709 was highly
refractory since
the patients had either to be intolerant
to their
most recent chemotherapy or had to have
progressed
on or within 90 days of their last
chemotherapy
cycle.
In Trial 709, as has been said,
the
primary endpoint was overall
survival. As stated
in the protocol, the primary analysis
method was a
stratified log-rank test. As is common in
oncology
trials, the protocol also stated that a
supportive
Cox regression analysis would be
conducted.
There were 2 co-primary
populations for
analysis, the overall population and a
subset of
patients with adenocarcinoma
histology. At least
900 deaths were required overall to
provide 90
percent power.
The secondary endpoints are
listed on this
27
slide, being time to treatment failure,
objective
response, quality of life, symptoms, and
safety.
Several subgroup analyses were
pre-planned
with the aim being to examine outcomes in
relation
to important clinical and biologic
factors, such as
EGFR expression and EGFR mutations, and
my
colleague, Dr. Ochs, will say more about
this later
in our presentation.
The data I will be presenting
today are
all those that accrued up to and
including the end
of October 2004. This date was chosen
because it
was estimated by this time the 900 deaths
we needed
for analysis would have occurred on the
database.
So, following data collection,
preliminary
data became available for the first time
in
mid-December 2004. At this time, median follow up
was 7 months, and we knew of 969 patient
deaths.
As can be seen on this slide,
patients in
Trial 709 were recruited mainly from
Central and
Eastern Europe and then Asia. As I mentioned
before, there were no U.S. sites in Trial
709, and
due to the approval of Iressa in December
2003,
28
only 1 percent of patients were recruited
in
Canada.
This slide shows the baseline
characteristics of the patients in Trial
709. The
median age was 62 years, about two-thirds
were
male, one-fifth were never smokers,
one-fifth were
of Asian descent, about half had
adenocarcinoma
histology, and about half had received
one prior
chemotherapy.
In line with our intent to
recruit a
highly refractory patient population, 90
percent of
the patients in 709 had progressed on or
within 90
days of their most recent
chemotherapy. Finally,
as you would expect in a large randomized
clinical
trial, the treatment groups were well
balanced at
baseline.
I would like to move on now to
look at
survival in the overall population. As you can
see, there was some improvement in
overall survival
in Iressa-treated patients with the
Kaplan-Meier
curves separating after about 4
months. However,
the magnitude of that improvement was not
29
sufficient to reach statistical
significance in the
primary stratified log-rank test,
however, the
supportive Cox regression analysis did
suggest
statistical significance.
Here are the survival curves
for the
co-primary population of patients with
adenocarcinoma histology. Again, there was some
improvement in overall survival in
Iressa-treated
patients, but the magnitude of that
improvement was
not sufficient to reach statistical
significance on
the primary stratified log-rank test.
Again, here, the supportive Cox
regression
analysis did suggest statistical
significance.
Moving on now to secondary
endpoint data,
tumor shrinkage in terms of response
rates was
significantly greater in Iressa-treated
patients
compared to placebo.
In terms of the time to
treatment failure
being the time from randomization to the
first
event that led to the cessation of
randomized
treatment, there was a statistically
significant
difference between the treatments with
the risk of
30
treatment failure being 18 percent lower
in
Iressa-treated patients compared to
placebo.
The reasons for treatment
failure are
shown on this slide. As can be seen, the primary
driver for treatment failure was
progression be it
either symptomatic or radiographic, with
approximately 56 percent progressing on
Iressa
compared to 70 percent progressing on
placebo.
As you would expect, Iressa
failed more
often due to adverse events than placebo,
and Other
on this slide refers to a number of items
including
lost to follow-up, noncompliance, and
withdrawal of
consent.
As you can see, there was no difference
between the two treatments in this
regard.
Turning now to quality-of-life
data, the
analyses of these data is currently
ongoing, but I
can share with you some initial
results. As you
can see, the primary quality of life
endpoints
being symptoms, overall quality of life,
and trial
outcome index, all tended to favor
Iressa-treated
patients although the treatment
differences were
relatively small.
As I mentioned before, several
subgroup
analyses were pre-planned. Now, before I run
through these data with you, it is
important to
31
emphasize that these analyses are not
retrospective, nor are they data driven.
The subsets were identified in
advance
based on what we saw in our Phase II
trials and
based upon findings on other drugs in the
same
class.
Furthermore, in analyzing these
subsets,
we have applied a rigorous statistical
approach
whereby we looked first for evidence of a
subset by
treatment interaction to give us
confidence that
the subsets are truly behaving
differently, and if
evidence exists, then, we go on to look at
detail
at the subsets.
It is important to recognize
that this is
a harder test to pass than simply having
a list of
subsets and looking for p less than
0.05. So, if
we do see differences in Trial 709, we
can be
reasonably confident that they are more
likely due
to a real drug effect than due to chance
alone.
This is the first of two slides
that show
subset analyses. For each subset analyzed, you can
see the hazard ratio and its confidence
limits and
the response rate in Iressa-treated
patients.
As you will recall, the hazard
ratio
measures the risk of death on
Iressa-treated
32
patients to placebo-treated patients, and
therefore, a hazard ratio of less than 1
to the
left of the vertical line shows a
treatment effect
in favor of Iressa, and a hazard ratio to
the right
of the vertical line shows a treatment
effect in
favor of placebo.
So, now while no subgroup
favored placebo,
there was clearly some variability in
survival
outcome.
This was most marked in terms of smoking
history where outcomes in never smokers
was
statistically different than outcomes in
ever
smokers.
This is the second slide
showing data in
subsets, the same format as the previous
slide.
Again, you can see there was variability
in
outcomes with, in this instance, it being
most
33
marked in terms of ethnicity where
patients of
Asian ethnic origin have statistically
different
outcomes to patients of non-Asian ethnic
origin.
Now, while the credibility of
subset
analyses is always a matter of debate in
any
clinical trial, in 709, the rigorous
approach we
have taken provides us with confidence
that the
differences we have seen are most likely due
to a
real effect of the drug, and less likely
due to
chance.
So, the findings we have seen
in Asians
and on smokers are therefore supported
statistically by the presence of subset
by
treatment interactions and also
clinically by prior
Phase II data that have consistently
shown
increased response rates in these
populations.
Furthermore, Trial 709 is
internally
consistent with respect to these subsets,
with
better time to treatment failure and a
two-fold
improvement in quality of life in
Iressa-treated
patients.
This slide shows survival
curves for never
34
and ever smokers. As you can see, there was a 33
percent reduction in the risk of death in
never
smoking patients treated with Iressa
compared to
placebo.
There was no significant difference in
ever smokers.
Similarly, this slide shows
survival
curves by ethnic origin. Again, you can see there
was a 34 percent reduction in the risk of
death in
Asian patients treated with Iressa
compared to
placebo, and there was no significant
difference in
non-Asian patients.
I would like to move on now to
look
briefly at the safety data in Trial
709. I should
note these data have become available
since we
compiled the briefing document, so they
won't be in
your papers.
The adverse event profile in
Trial 709 is
consistent with the established safety
profile for
Iressa with the most common adverse
events being
rash and diarrhea.
Notably, there was little
difference
between the treatments in terms of
serious adverse
35
events, adverse events leading to
withdrawal, and
the incidence of interstitial lung
disease.
Here is a summary of the most
common
adverse events in the trial ordered from
highest to
lowest frequency in Iressa-treated
subjects.
As you can see, with the exception
of rash
and diarrhea, which I just mentioned,
there is
little difference between Iressa and
placebo-treated patients in terms of the
adverse
event reporting. In particular, there were
relatively few Grade 3/4 adverse events
in
Iressa-treated subjects.
This list of adverse events
continues on
this slide where again it can be seen
there is
little difference between Iressa and
placebo-treated subjects.
As I mentioned at the outset,
the
preliminary data we saw on December 16th
were
validated and finalized as of the 2nd of
February
2005.
These final data confirmed a total of 976
deaths occurring on or before the October
2004 data
cutoff.
With only 7 additional deaths, it is
36
obviously not surprising that the
findings based on
the preliminary data remain unchanged.
On reviewing the data in
December, the
Independent Data Monitoring Committee
recommended
that further follow-up of Trial 709
should be
obtained.
Having seen somewhat late separation in
the Kaplan-Meier curve, they were
unwilling to rule
out
that further separation could occur with more
follow-up.
Hence, survival data were
updated as of
the end of January, which provided for a
further 3
months of follow-up, taking median
follow-up to 10
months and overall mortality in the trial
to 70
percent.
As you can see, these further
data are
consistent with the planned protocol
analysis, and
despite increased crossover in the
placebo arm to
Iressa, variability in survival outcomes
continues
to be seen.
To briefly summarize what we
have shared
today, the data seen on December 16
showed some
improvement in survival in Iressa-treated
patients,
37
but the magnitude of that improvement was
not
sufficient to reach statistical
significance in the
primary stratified log-rank test.
Overall, however, considering
both primary
and secondary endpoints, these data
showed that
Iressa was efficacious in the population
study, but
there was marked variability in survival
outcomes.
So, with that, I would like to
thank you
for your attention and hand over to my
colleague,
Dr. Ochs.
Judy.
Clinical Actions and
Implications
DR. OCHS: Thank you, Kevin.
In this part of our
presentation, I would
like to briefly summarize AstraZeneca's
actions to
communicate the results of Trial 709 to
the
oncology community. Following this, I would like
to give an overview of the clinical
implications of
the Trial 709 data, review some of the
immediately
relevant emerging science, and conclude
with our
proposed or ongoing development
proposals.
In agreement with the FDA,
AstraZeneca
concluded that it was in the best
interest of
38
patients that the information on Trial
709 be
rapidly, extensively, and clearly
communicated.
On December 17th, a Dear Doctor
letter
approved by the FDA was distributed by
AstraZeneca.
This communication provided physicians
with the
needed information to enable them to make
the most
appropriate treatment decisions. The expectation
was that this communication would greatly
reduce
the number of patients receiving Iressa
for the
first time.
In addition, AstraZeneca would
provide to
the FDA, prescription data every two
weeks to be
able to assess the continuing impact of
the
communications.
It was also agreed that a key
goal was to
maintain Iressa availability to those
patients
already benefiting who would wish to
continue and
had concerns about possible Iressa
availability.
A commitment was given to the
FDA that
AstraZeneca would rapidly provide them
with all of
the data as it became available to allow
them a
thorough and informed analysis.
Upon public release of the top
line Trial
709 survival results a series of
extensive
communications were simultaneously begun
and are
39
listed on this slide, and were previously
mentioned
by Dr. Pazdur.
Taken as a whole these actions
were
designed to ensure that relevant
physicians would
be aware of the results and be reminded
that
alternative therapeutic options with
proven
survival benefits should be considered.
On January 6, the FDA and
AstraZeneca met
and
agreed upon the following steps for continuing
communication of the Trial 709 data. A public
disclosure of the then available results
would be
made at the first available scheduled
ODAC meeting,
today, acknowledging that the further
trial data
would still be pending.
Ongoing communication of the
Dear Doctor
letter was to be done using journal
placement and
the full clinical data would be submitted
and
presented at scientific meetings and
published in
refereed scientific journals as soon as
possible.
Abstracts have been submitted
to the AACR
meeting, as well as the World Lung Cancer
Conference. A full publication submission is
planed in the May-June time frame.
Here is a copy of the Dear
Doctor letter,
which I realize you cannot read. The letter,
40
however, does include the survival results
in the
overall and adenocarcinoma subpopulation
along with
median survival and respective hazard
ratios.
The sentence highlighted in red
above is
included in the body of the letter and
urges
physicians to consider other treatment
options.
This is how the letter is being displayed
in the 10
most widely read oncology journals, and a
list of
these journals is shown in the next
slide.
The impact on Iressa usage has
been marked
in the 10 weeks since the Dear Doctor
letter was
first sent out. There has already been a
significant reduction in the
prescriptions written
for Iressa, and our internal AZ usage
data also
indicates marked reduction.
Market research, that we have just
41
obtained from 100 community oncologists,
indicates
that the great majority are aware of the
data
contained in the Dear Doctor letter and
have
modified their treatment practice
accordingly.
Thus, all of the agreed upon
communication
actions have been set in motion, and the
available
information suggests that the oncology
community is
aware of and acting on the information.
The larger question is now
being asked:
What are the clinical implications of the
Trial 709
data, and what are the next steps? These are
clearly important questions for
oncologists and
patients since Iressa possesses
significant durable
anti-tumor activity which has greatly
benefited
some patients and some patient subsets.
Yet, in Trial 709, Iressa did
not meet the
statistically defined survival endpoint
in an
unselected patient population.
Advances in understanding of
the molecular
biology in this area of EGFR inhibition,
as well as
in the area of non-small cell lung
cancer, are
occurring rapidly and have the potential
to better
42
select or predict those patients who
would benefit
beyond, or in addition to, clinical
characteristics.
What are the questions that we are asking
as we seek to understand the Trial 709
outcomes,
and not wrongly or prematurely make
conclusions
about the actual role or place of Iressa,
an agent
with anti-tumor activity in the treatment
of a
disease with a continuing poor
prognosis? Why did
this result occur?
How does this result compare
with our
other data on Iressa in non-small
cell? Were the
findings in our trial due to play of chance? Was
the dose selection appropriate? Were there
methodologic issues, such as the trial
population
and where the trial was conducted of any
potential
impact on the findings?
What biologic data may be
available now
and in the future to help better
understand the
clinical outcomes, and what further
relevant
clinical data in the recurrent non-small
cell lung
cancer setting are expected?
Firstly, how does the survival
outcome
seen in Trial 709 compare to other data
with
Iressa?
As was previously mentioned by Dr. Scott
43
in our Phase II program, a striking and
unanticipated finding was the apparent
high rate of
response in patients with certain
clinical
characteristics.
It can be seen if one compares
these Phase
II response rates with those in Trial
709, and the
Phase II results are in the right-hand
column in
yellow, and the 709 results in the middle
column in
white, that the same patient groups
continued to
show higher response rates.
In addition to these higher
response
rates, the subgroups having the highest
response
rates experienced the greatest benefit in
survival.
The patient subgroup with the highest
response rate
were the never smokers, and as previously
noted,
the survival in this subgroup was significantly
increased.
Similar trend, although not of
the same
magnitude, of survival benefit was seen
in women
44
and with the adenocarcinoma group.
Continuing with this line of
inquiry,
higher response rates and statistically
significant
survival results and benefit were seen in
those
patients of Asian descent.
Could chance have played a role
as the
defined survival endpoint was so narrowly
missed?
Trial 709 and the erlotinib trial BR21
are the only
two Phase III survival trials which
compare an oral
EGFR inhibitor with placebo in the
recurrent
non-small cell lung cancer patient
population.
Both Iressa and erlotinib have
similar
overall response rates as can be seen in
the
right-hand portion of the slide. The erlotinib
trial did reach statistical significance
for the
overall population.
Juxtaposing overall survival
hazard ratios
as we have done in this slide shows that
while the
point estimates differ, there is a high
degree of
overlap in the confidence intervals. The small
confidence interval in Trial 709 reflects
the
larger trial size in 709, which is almost
twice
45
that of the BR21 trial.
Dose selection. Since there appears to be
a difference in magnitude of survival
benefit in
BR21 compared to Trial 709, questions
about the
adequacy of the Iressa dose have arisen
irrespective of the data used to support
its use in
this trial.
The erlotinib dose used was at
the maximal
tolerated dose, while the Iressa dose is
one-third
the maximal tolerated dose, reflecting
different
development strategies.
As you might guess, we have
gone back and
re-evaluated our prior experience in
light of the
current data. Our extensive Phase I
program had 280
patients, and these patients received
doses ranging
from 50 mg to 1,000 mg.
Responses and durable stable
disease first
were seen at the 150 mg dose level. There was no
dose response evident from 150 mg through
1,000 mg
with respect to partial response rates,
partial
response rates plus stable disease rates,
or the
duration on Iressa therapy.
In our Phase II trials, as
previously
mentioned, we formally compared the 250
and 500 mg
dosage.
250 mg was chosen as it was above the 150
46
minimum dose that we saw responses and
stable
disease at, and 500 mg dose was chosen in
part
because of minimizing the amount of
patient
interruptions of therapy due to toxicity.
We found no difference in
efficacy
including survival although the adverse
events and
therapy interruptions were more frequent
at the
higher 500 mg dose.
Admittedly, however, we have
not
rigorously evaluated doses above 500 mg,
and it is
unknown if doses above 500 mg would
achieve better
overall or patient subset survival
outcomes. Due
to the lack of data, we cannot rule this
out
entirely.
Speculatively, can the
inability to
achieve statistically significant
survival be
explained by too few patients likely to
benefit
based on their advanced disease status
with
refractoriness as specified in our
patient
47
inclusion criteria.
Another area to further explore
are the
impact of environmental factors, such as
smoking,
as it relates to various geographic
regions where
the trial was conducted.
As Mr. Carroll showed, over
one-third of
the patients on Trial 709 were from
Eastern Europe
where the median pack year exposure was
very high.
Patients with the highest smoking
exposure appear
less likely to benefit from EGFR
inhibitor therapy.
We have looked at our data and found
a
continuous spectrum in terms of survival
benefit,
with the greatest survival benefit
appearing in
never smokings, but it continues with the
amount of
exposure to smoke.
So, what can we conclude at this point?
Iressa is an active agent, the response
data are
consistent in our Phase II and III
trials. The
patients most likely to benefit are those
patients
who never smoked and those of Asian
ethnicity.
With these consistent findings,
using an
agent that inhibits a specific receptor
and
48
pathway, it is logical to assume that
there is an
underlying biologic basis. In the last 10 months,
two areas of translational research have
been
fruitful and may be useful in better
understanding
the clinical data in our Phase III
program in Trial
709, as well as guide therapy in our
future
development.
The two biomarkers of most
promise
currently are EGFR expression and the
EGFR
mutations. Published Iressa Phase II data did not
appear to show definitive correlation of
EGFR
expression with response, but tumor samples
were
not available from all patients, and the
trials
were not controlled.
Recently, however, results
relating EGFR
expression to survival outcomes were
included in
the erlotinib label.
The second promising biomarker
are
activating mutations. These were first described
approximately 10 months ago in responding
Iressa
patients.
There are other promising, but more
exploratory biomarkers that are included
in the
49
Iressa science program including gene
copy number
and dimerization patients, but again
these remain
more exploratory.
What I would like to do now is show you
from the erlotinib label--and I have
included the
three graphs they have relating to EGFR
expression--and to ensure perfect
synchronicity and
accuracy, I am going to read the portion
for you
for all of those of you who can't read
the lower
right-hand column.
What we see here are three
graphs. The
graph to the upper far left is the graph
of the
patients who had positive EGFR expression
in their
tumors, with the lower part of the
Kaplan-Meier
showing the patients treated with
placebo.
The graph to your far right, on
the
upperhand side is the patients who were
EGFR
expression-negative compared to placebo. The lower
lefthand is those patients that they did
not have
EGFR expression data on.
As stated in the label, Tarceva
prolonged
survival in the EGFR-positive subgroup
and the
50
subgroup whose EGFR status was
unmeasured, but did
not appear to have an effect on survival
in the
EGFR-negative subgroup. However, the confidence
intervals for the EGFR-positive,
negative, and
unmeasured subgroups are wide and
overlap, so that
a survival benefit due to Tarceva in the
EGFR-negative subgroup cannot be
excluded.
It needs to be said that a
positive EGFR
expression status in this study was
defined as
having at least 10 percent of cells
staining
positive for EGFR in contrast to the 1
percent
cutoff specified in the DAKO EGFR pharmDx
kit
instructions.
The use of the pharmDx kit has
not been
validated for use in non-small cell. Accordingly,
the data to date are inconclusive, but
tantalizing
as to the predictive nature of EGFR
testing.
In this trial, as in Trial 709,
the tumor
sample collection was not mandatory, and
thus the
number of samples is less than the number
of
enrolled patients.
This is a busy slide and
summarizes a very
51
busy area of research in the 10 months
since
mutations were first described. As noted on this
slide, mutation appears to occur almost
exclusively
in non-small cell lung cancer. The mutation is
activating and in the ATP-binding site,
which is
where Iressa's activity occurs.
I mentioned that the mutation
was first
described in patients with rapid,
dramatic and
prolonged responses to Iressa. The increased
frequency of the mutation occurs in
patient subsets
where Iressa responses are most frequent
and where
the survival benefit is most likely to be
seen,
that is, those patients who were never
smokers,
patients of Asian descent, women, and
adenocarcinoma histology.
There are actually two papers out
this
week looking at smoking status in
relationship to
the presence of these activating
mutations, and
depending on the paper, a minimum of 25
percent to
75 percent of patients in different
geographic
regions who were never smokers have the
mutation
present.
While patients whose tumors
possess this
type of somatic mutation appeared to be
much more
likely to have a response, all patients
with
52
mutations do not have a response. We have recently
looked at our IDEAL II data, and in the
small
subset with 14 mutations that we
detected, 6 of
these patients had prolonged partial
responses.
Again, where are we? EGFR expression
appears to be associated with increased
survival.
EGFR mutations appear to explain some,
but not all,
of the responses to Iressa.
Outcomes in Trial 709, comparing Iressa to
placebo, will be explored in terms of
EGFR
expression, activating mutation, and
other
biomarkers.
We anticipate that this data
will be
available in June 2005. We have collected close to
600 tumor samples. Approximately 400 of them we
estimated based on our past experience
will be
fully evaluable for EGFR expression, and
200 for
mutation status.
It is hoped that these results
may provide
53
further insight into the clinical
outcomes that we
have seen in Trial 709.
Thus, with these current
clinical and
translational data, what prospective
studies are
underway or could be considered?
One proposal would be to
evaluate patients
with metastatic disease and compare the
outcomes of
Iressa with chemotherapy. Mandatory tissue
collection is an obvious requirement to
evaluate
the utility of biomarkers with respect to
both
outcomes in both the chemotherapy-treated
patients
and in patients with EGFR expression or
overexpression.
Targeted studies in patient
populations is
another obvious way to proceed. We have an ongoing
Phase II trial which is enrolling
patients who are
mutation-positive, another trial that is
a trial
that should be considered is that in
patients who
are never smokers.
Never smokers represent 20
percent of the
U.S. population of non-small cell lung
cancer
patients.
Finally, specific trials in the
Asian
populations to define the role of Iressa
in the
first line setting appear warranted. Here, too,
54
translational studies would be integral
to the
trial.
There are already several trials being
conducted in Asia, as you might
anticipate.
A clinical question of
increasing
relevance that hasn't been answered to
date is that
of comparing both survival outcome and
toxicities
of Iressa or any EGFR inhibitor with
single agent
chemotherapy.
Trial 721, as previously noted
by Dr.
Scott, is a randomized Phase III
post-approval
commitment trial which compares Iressa to
docetaxel. This trial will complete patient
enrollment by the end of the summer, and
an interim
survival analysis is expected this May or
June.
Trial 721's principal
investigators and
steering committees have reviewed the
Trial 709
data and continue to support this trial. Another
similar trial is being conducted entirely
in Japan.
Some clinical support to
continue at this
55
dose is mature Phase II data in a
Caucasian and
Hispanic patient population, which has
recently
matured and become available. In addition
to
showing comparability with the primary
symptom
endpoint, comparable outcomes were seen
with
response rates, time to progression, and
overall
survival.
The next slide is a
Kaplan-Meier survival
curve from this trial, and it is easy to
see the
comparability of these trial
results. With a
median follow-up of 9 months and 55
percent overall
mortality, there are no differences between Iressa
and docetaxel.
The overall survival with
docetaxel is
consistent with that previously reported
with this
agent and in this clinical setting. Although the
trial is small, if Iressa was behaving as
a
placebo, then, one would have expected
Iressa to
have performed substantially worse in
both time to
progression, as well as overall survival.
Back to our original
question: Where are
we now?
Well tolerated agents in the
EGFR
inhibitor class of agents are now an
accepted
addition to the therapeutic armamentarium
of
56
practicing oncologists and clinical trial
investigators.
Clinical and translational data
are
pointing the way to the most appropriate
and
optimal use of Iressa. AstraZeneca and our
clinical investigators remain committed
to this and
other biologically targeted agents as the
way to
the future.
Thank you.
DR. PAZDUR: Silvana, I am sorry, I didn't
realize there was more from AstraZeneca,
but if we
want to have some discussion or
clarification
before the open public hearing, that
would be
appropriate.
Summary
DR. SCOTT: Thank you, Dr. Ochs.
As you have heard from both Mr.
Carroll
and Dr. Ochs, there is a lot of work
ongoing to
fully understand Trial 709, and there are
other
57
trials, such as Trial 503, that provide
supportive
information, and Trial 721, which is also
part of
our Subpart H commitment to the FDA.
This slide summarizes some key
milestones
that will be occurring. It is expected that the
complete data from Trial 709 and Trial
503 will be
with the FDA in June for their
review. After that
time, we expect to discuss labeling
updates as
appropriate based on the final data
findings.
It is expected that the Subpart
H
commitment trial, Trial 721, will deliver
its final
survival data in November of 2006.
While the drug development road
for Iressa
has not been straightforward or without
its
surprises, the development program for
this agent
has provided a great deal of valuable
information
about non-small cell lung cancer and the
EGFR
target.
Iressa is an active and well
tolerated
agent, and the lung cancer community has
urged us
to continue the development of this drug,
and we
are committed to doing so.
Trial 709 has provided
important patient
selection information in a controlled
randomized
setting that may in the future help us
write
58
appropriate labeling to guide the
clinical use of
Iressa.
You have also heard today the
critical
information regarding EGFR expression and
mutation
status is yet to be delivered from this
trial.
Trial 721, the head-to-head
trial versus
docetaxel can provide confirmatory
evidence of the
effectiveness of Iressa. As outlined, the
development program for Iressa will help
in
identifying those patients who are most
likely to
benefit from Iressa.
AstraZeneca rapidly and
thoroughly
disseminated information to oncologists
about Trial
709 to ensure informed treatment
decisions would be
made while further analysis were
underway.
As the patients responsive to
Iressa will
tell us, and their physicians will
support, Iressa
remains an important treatment option for
non-small
cell lung cancer.
We thank the committee for
their attention
and welcome any questions at this time.
Committee Questions
DR. MARTINO: Dr. Ochs, do one thing for
me before you leave. A slide was shown by--Dr.
Ochs actually had the slide up--where you
59
demonstrated what has been done to
disseminate this
information, if you would just flash that
one more
time.
I will allow the committee to
ask
questions. We actually have no time allotted for
that, so please keep your questions
pertinent to
today's issue, which really is has this
information
been appropriately disseminated.
The slide that I want you all
to just
notice are the things that they have, in
fact, done
to disseminate this information. Rick, can you
simultaneously just remind the group what
the FDA
has done from its side in terms of disseminating
the information, so that everyone is sort
of up to
date.
DR. PAZDUR: We have notified shortly when
60
we were in receipt of this information,
an e-mail
went out from the FDA to ASCO members
notifying
them on that day that we received the
information
of the study results and alternative
treatment.
We have a letter posted on our
website
that is included in your packet.
DR. MARTINO: So, then, from the FDA's
side, the information has gone out to
physicians
primarily, as well as the website.
DR. PAZDUR: Correct.
DR. MARTINO: And from AstraZeneca,
information has been provided to
physicians, as
well as to the lay public.
DR. OCHS: Yes.
DR. MARTINO: At this point, I will take
some questions, but please keep them
brief and
succinct.
Dr. Hussain, you are first.
DR. HUSSAIN: It is a question to either
Dr. Mark or Dr. Ochs. When you pointed out that
you are possibly thinking about targeted
population, I saw that there were no women
61
mentioned and no adenocarcinoma.
Does that mean if you were a
smoker and a
woman, that the smoker component takes
over as far
as your potential benefit, or that if you
are an
Asian and a smoker, then, the smoker
takes over?
DR. OCHS: I think I will let Dr. Carroll
discuss that particular issue since there
is a lot
of interconnection and interplay.
MR. CARROLL: Thank you for your question.
Of course, it is very important, I mean
it is one
that we need to look at more closely,
what is the
interplay between the factors of
interest, be they
Asians, be adenocarcinoma, gender.
The data, as I said, were
finalized
only--I am not sure--four or so weeks
ago, and that
kind of analysis requires multivariate
analysis to
actually see which factors are
contributing, which
are the ones that are predicting the
treatment
effect.
That is something that we do
plan to do in
the next coming weeks and months to
provide that
data to the FDA, so we can answer the
very
62
important question that you have raised,
because I
am not sure we have the answer to that
today.
DR. MARTINO: Dr. Perry.
DR. PERRY: I am not sure who gets this
question, but I have been under the
impression that
in Europe particularly, the incidence of
squamous
cell carcinoma was considerably higher
than in the
United States, so I am somewhat surprised
of a 48
percent incidence of adenocarcinoma histology
worldwide, particularly when two-thirds
of the
patients seem to be from Europe.
How do you know that these are
adenocarcinomas, is this the local
pathologist's
interpretation, and are they inclined to overread
them as adenocarcinomas rather than as
non-small
cell carcinomas not otherwise specified?
DR. SCOTT: I will ask Dr. Alan Barge to
come and speak to that point.
DR. BARGE: Thank you.
Alan Barge,
AstraZeneca.
We have not done central
pathology review.
All of the diagnoses were the ones that
were
63
confirmed by the hospital pathologists,
so we
couldn't answer your question directly, I
am
afraid.
DR. MARTINO: Dr. Rodriguez.
DR. RODRIGUEZ: I just wanted some
clarification about the actual trial
design, and
just have a few questions which might be
relevant
because this was done by a variety of
cultural
groups.
Were the patients and the
investigators
both blinded to the assignment to
placebo?
DR. SCOTT: Yes, it was a randomized
double-blind trial.
DR. RODRIGUEZ: How was compliance
confirmed in the participants?
DR. SCOTT: Nick Botwood will come to the
stand.
DR. BOTWOOD: Thank you.
Nick Botwood,
AstraZeneca. We did look at compliance on this
trial and found that over 90 percent of
the
patients were compliant and had taken at
least 95
percent of their medication.
This was based primarily on
data that we
collected in the CRF in terms of any
documented
dose interruptions for whatever reason,
and then we
64
went on to further validate that, to
actually look
at the number of tablets that were
returned and
looked at the number of tablets that had
actually
been prescribed to validate that what was
in the
CRF was actually the correct information.
DR. RODRIGUEZ: Along those lines, was
there a required or concurrent diarrhea
prophylaxis
program, and was compliance to that also
monitored?
DR. BOTWOOD: That wasn't, no.
DR. RODRIGUEZ: It is interesting because
your failure to treatment has a
significantly
different profile with regards to
symptoms and
adverse events. It seems that the patients on the
Iressa arm, a higher proportion were
taken off
study because of those problems, is that
correct?
That is what your bar graph seemed to
show.
DR. BOTWOOD: Kevin Carroll can answer
that question, please.
MR. CARROLL: If I am correct, you are
65
asking whether there was a difference in
withdrawal
due to--
DR. RODRIGUEZ: Yes, side effects.
MR. CARROLL: Side effects.
As I showed
when we went through the adverse event
data, there
was very little difference between the
two
treatments in terms of withdrawal due to
adverse
events, and in terms of the data that we
obtained
on time to treatment failure, there were,
in fact,
fewer--Iressa failed fewer patients due
to
progression than placebo, so I don't
think the
difference was there in the way that
perhaps you
think.
DR. MARTINO: Dr. Levine.
DR. LEVINE: I also have several
questions. First, you mentioned crossover. How
many of these placebo patients did cross
over to
Iressa?
DR. SCOTT: Dr. Botwood.
DR. BOTWOOD: Yes, thank you. The rate of
crossover from placebo to Iressa in this
trial was
only 3 percent.
DR. LEVINE: Three.
Do you have data on
other treatment beyond, you know,
crossover to
anything?
66
DR. BOTWOOD: Yes, we do.
The number of
patients that went on to receive any
subsequent
chemotherapy was 10 percent, and this was
balanced
between the Iressa and placebo arm.
DR. LEVINE: Just to further that a little
bit, even complementary therapies in
Asia, and so
forth, do you have data on that, green
tea?
DR. BOTWOOD: It was extremely small.
DR. LEVINE: My other question related to
the concept of secondary smoke. In Eastern Europe
and in Asia, where so many of the
population smoke,
even individuals who say that they
weren't smokers
may have been exposed, and therefore, did
you look
at cotinine levels or anything? That might be
something to explore, or did you look at
that?
DR. BARGE: I am afraid we haven't looked
at that. When we looked at the smoking
demography
of the patients from Eastern Europe,
approximately
85 percent of the patients from Eastern
Europe were
67
heavy smokers, and they had a higher
median year
exposure than the patients from other
regions, but
that is as far as we got, I am afraid.
DR. MARTINO: Dr. D'Agostino?
DR. D'AGOSTINO: Yes. I
am having a hard
time keeping my questions solely to the
material
that has been circulated as opposed to
asking a
million questions about the study, but
the question
I do have in terms of the reporting of
the data,
you may have said it, and I am sorry if I
missed
it, you did have the expected number of
deaths, you
wanted 690 or whatever, 960, and you got
more.
I understand that the study did
run its
course, and then you did an analysis with
unclean
data or not completely clean data, and
then later
on had clean data, or was the analysis
you are
reporting an interim analysis?
DR. SCOTT: The analysis that we reported
on in December was not an interim
analysis. It was
based on final survival data, but it had
been yet
to be validated.
DR. D'AGOSTINO: Okay.
So, it was the
68
validation. Thank you.
DR. MARTINO: Dr. Proschan.
DR. PROSCHAN: You mentioned that the
Phase II trials identified subgroups, and
ethnicity
was one of them. I am wondering if, at
that time,
you specifically decided to break it into
Asian
versus non-Asian, and why do you think
there is a
difference?
DR. SCOTT: We can have Mr. Carroll talk
about the rationale behind the subgroups
that we
planned for Trial 709, and then perhaps
have Alan
Barge talk about why we think so.
MR. CARROLL: The subsets that we have
looked at in Trial 709, all of them we
have shared
with you today, I have not shared a
subset of the
subsets, of course, and they were
determined
primarily by what we saw in our Phase II
data, and
also information that came out in June of
this year
on the BR21 trial, as described by Dr.
Ochs.
There, there was an evaluation of
Asians
and non-Asians, and that, in addition to
our
findings in the IDEAL trials where our
Japanese
69
patients had a much higher response rate
was a
motivation to look at that subset amongst
others
that were deemed to be clinically
relevant.
Perhaps I can now turn to my
colleague,
Dr. Barge, to answer the second part of
your
question.
DR. BARGE: Yes, thank you. There is a
good deal of speculation as to why
patients of
Asian ethnic origin appear to do better
on this
class of drug. There have been some quite
interesting publications very recently. In fact,
this week there was a publication from
Dr. Gazda
[ph] at UT-Southwestern. His group showed that the
frequency of activating mutations of the
kind that
Dr. Ochs described is much higher in
Asian
populations, particularly female Asians,
and
particularly female Asians with
adenocarcinoma.
The Phase II studies that we
conducted in
various Asian countries all show that the
frequency
of responses are much higher in those
populations,
and we have seen response rates as high
as 60 or
even 80 percent in selected populations
of Asian
70
nonsmoking females.
Whether or not that is all
driven by
activating mutations we don't know, but
that is
certainly a very strong hypothesis at the
moment.
DR. MARTINO: Mrs. Ross.
MRS. ROSS: Thank you, Madam Chair.
If I understand correctly, the
primary
purpose of this hearing is to evaluate or
just to
discuss the transparency of the
post-approval
process and the adequacy of the
notifications.
In that regard, I would like to
advise the
rest of the panel of other steps that were
indeed
taken by both AstraZeneca and the FDA,
and I would
like to thank Dr. Pazdur in particular
for his help
on this.
As the only lung cancer
advocacy
organization nationwide, we started
receiving many
phone calls from patients who were
somewhat
panicked when they heard the news in the
press that
Iressa might be pulled. The press always leaps to
the worst possible conclusion, as you all
know.
These people were discussing
stockpiling
71
drugs, buying them in Japan. There was a lot of
panic out there. Dr. Pazdur responded,
and
AstraZeneca did, by helping us draft more
information, more plain English
information to put
up on our website and to tell people over
the phone
when they called in a state of panic
about Iressa.
I think that should be
noted. I think
that overall, the process was
extraordinarily
transparent and more than adequate in
dealing with
the situation. Again, I would just like to thank
FDA and AstraZeneca for all they did.
DR. MARTINO: Dr. Temple, did you want to
make a comment?
DR. TEMPLE: Just one question. We
certainly never at any time thought that
someone
who had apparently responded to the drug
should
lose access to it. That was never in doubt.
But I wanted to ask you about
where
AstraZeneca is at the moment. This was, shall we
say, an optimistic presentation. The study, after
all, failed. You had opportunities to identify
subsets before the study that would be
your primary
72
analysis, but you didn't think that they
were good
enough to do that.
So, these are now--it's an
important
distinction, Ralph may want to comment
more--these
are after-the-fact subset analyses in a
study that
did not win. That is different from subset
analyses in a study that did win.
But what I really want to know
is where do
you
come out on the question of new patients with
non-small cell lung cancer being started
on Iressa
now.
The material you put out says you should
consider other drugs. Fine.
But would it be your view that
at the
present time, optimism about the future
and data
that might come forward notwithstanding,
a person
with this disease should really not be
started on
Iressa, would that be your view, or is
that not
your view anymore?
DR. SCOTT: Our view is that what was
stated in the Dear Doctor letter then is
what is
today, that physicians should consider
other
options armed with the information from
this
73
particular trial.
If I could ask Dr. Kris to come
up and
talk about how this has played out in his
practice,
maybe Dr. Burris, as well.
DR. KRIS: To answer your question, Dr.
Temple, I think the most important thing
is to put
this into a context of what is available
for a
patient with advanced non-small cell lung
cancer
particularly after the failure of initial
therapy.
I think that the information
that we have
today is that there are some patients,
those with
an EGFR mutation, that have, and the
literature
today says that they have an 89 percent
chance of
having a response, and in those patients,
when you
look at their duration of response and
survival, it
is clearly prolonged. In the trials that looked at
survival in mutation positive and
negative people
being treated, it is much better with
treatment.
So, as a clinician, my first
point is to
find those people that have that
extraordinary
chance of benefit, that is,
mutation-positive
people, and the two surrogates for
positive
74
mutation we have today, that is, never
smoking
status for U.S. population and worldwide,
is
probably Asian, and it is not simply
Japanese.
There are reports now from Taiwan, from
China,
Singapore.
DR. TEMPLE: Let me be clear, though. You
are looking at the mutation status of the
people
in--some of the people anyway, about 200
you
said--in the trial, and maybe that will
be
overwhelming and knock everybody's eyes
out.
But at the moment you have no
prospective
data on that subgroup for survival.
DR. KRIS: The only prospective data that
exists on the treatment of
mutation-positive
patients is, frankly, an extrapolation to
the never
smoking patients.
DR. TEMPLE: I understand.
DR. KRIS: But those are
placebo-controlled trials.
DR. TEMPLE: But what I am really asking
is what you really mean, and we will
probably have
to have subsequent discussions, one might
say that
75
you should use the drug with very similar
properties, similar mechanism, et cetera,
that has
actually been shown to improve survival.
Are you saying something to the
contrary
or not?
I don't think it is clear yet. I
sort of
thought it was clear, but from your
presentation, I
don't.
DR. KRIS: Well, I frankly think that the
most critical slide there was looking at
the hazard
ratios for the two substances, for
gefitinib and
erlotinib. I am putting my clinician hat on, it is
not an AstraZeneca hat right now, and that
clinician's hat is that there is effect
there.
You can argue the p value of
0.04 versus
0.07, and there are people here that can
do that
much better than I, but from the
clinician
standpoint, you have to make that
choice. But you
must remember that this isn't--you also
have a
patient, you have a man with a squamous
cancer
sitting in your office that is smoking
today, and
his likelihood of benefit by the
literature is
extraordinarily small, well under 5
percent.
So, for that patient, you are
going to
make another choice, so that the choice
for the
patient is not going to be decided by
this trial as
76
a clinician.
DR. TEMPLE: I am really asking about what
is your view now, is on a person who is a
candidate
for an EGFR order of treatment now based
on
available data. I actually thought you thought
that for the moment, one should use the
drug that
actually won, but I no longer perceive
that in your
presentation.
DR. KRIS: I am talking about from a
clinician's standpoint, and I interpret
the whole
of the data as unbelievably
consistent. I mean I
think it is extraordinary that when you
look at the
mutations, when you look at the response
rates
across country, across drug, it is how
consistent
it is, particularly the smoking
observation.
DR. TEMPLE: The pattern may be the same.
It may just be that this drug doesn't
work as well
as the other one even though the pattern
is the
same.
It is possible.
DR. KRIS: Again, I can't rule out that
possibility, but you can't look at any
one piece of
data in my estimation, and this is one
piece of
data today.
DR. PAZDUR: But Mark, you pointed out
that you may look at the mutational
status in
77
making a decision, but really, in the
United
States, only a small number of people
really have
that available to them.
DR. KRIS: Rick, from a practical
standpoint, I don't look at the mutation
status.
We can do that at our institution, but it
is a very
limited availability right now. The decision is
made on clinical grounds, and the
surrogates for
mutation we have today, and they are two.
They are
never smoking status and Asian birth, and
that is
how we make our decision.
DR. PAZDUR: I have another question for
AstraZeneca. In your presentation, you noted a
decrease in new prescriptions. Could you tell us
what you mean by new prescriptions for
Iressa, does
that mean new patients or simply renewal
of
78
prescriptions of existing patients that
are already
on it, or can you distinguish between
that?
DR. SCOTT: The new prescriptions are not
new patients, they are a mixture of
patients that
are getting a refill of prescriptions,
because
every time a new script is written, it
could be for
a patient that didn't have a refill, and
it could
be for new patients, but I will ask
Carolyn
Fitzsimons to talk about that data, how
we are
interpreting it with the availability of
other
information that is indicative of most--
DR. PAZDUR: Because we are very much
interested, following up on Bob's
question, how
many new patients--
DR. SCOTT: Right, and I will ask Carolyn
Fitzsimons to come and speak to that.
MS. FITZSIMONS: Thank you.
Carolyn
Fitzsimons, AstraZeneca.
If I can just show the slide as
to what is
happening with the prescription data and
try and
answer your question, Dr. Pazdur, in terms of
specifically new patients.
We have not been able to secure
a source
to actually define new patients, so we
have to take
the new prescription data as indicative
of what is
79
happening in the marketplace.
The new prescription data, as
Mark has
just explained, is not wholly attributed
for by new
patients.
It encompasses every time a new
prescription is written, so a repeat
prescription.
From the data that we have and
is shown
here, on the significant decrease that we
have seen
in new prescriptions, a 58 percent
decrease since
the
announcements of Trial 709.
It is our belief, based upon
the duration
of therapy of an Iressa patient who is
currently
receiving the product, that the majority
of these
prescriptions are now being written for
patients
who were prescribed Iressa prior to the
announcements of Trial 709, and are
receiving
ongoing therapy from consultations with
their
physician, therefore, we assume they are
deemed to
be benefiting.
We have conducted some market
research
80
earlier in February to try and further
establish
what is happening with new patients, and
from that
data, we have established that physicians
are aware
of the Trial 709 results, and are not
longer
choosing Iressa as their EGFR inhibitor
of choice,
they are choosing erlotinib, and 86
percent of them
indicated that from the market research.
DR. SCOTT:
If I could ask Skip Burris to
come up and talk about what has happened
at
Tennessee Oncology. Although it is an n of 1, it
is reflective.
DR. BURRIS: Thank you, Mark. It is an n
of 1, but it is a large group of 36
practicing
oncologists, and it gets to Dr. Temple's
questions,
and he and Mark were certainly talking
about one
issue, but we felt the need to issue some
guidelines.
Certainly those guidelines were
that those
patients that were being treated with
Iressa,
should be continued on Iressa, that those
patients
who fit into a class where it is felt it
appropriate that an EGFR inhibitor should
be
81
utilized, that erlotinib or Tarceva
would, in fact,
be the preferred agent in the short term,
that
there should be consideration given based
on the
data between the two agents, that, in
fact, if
patients were intolerant of one or the
other, to
switch to the other in the class. If fact, that
has occurred in at least several
patients.
Lastly, and maybe most
importantly, is the
fact that as a conscious decision,
analyzing the
data within our group, we have continued
to accrue
and randomize patients on a count done
quickly
yesterday, 9 patients, in fact,
randomized to
Iressa in a controlled Phase III trial in
patients
with refractory lung cancer.
So, the believe of the group,
as Mark
alluded to, certainly subsets that will
benefit,
but we have continued to accrue to trials
comparing
a new agent with Iressa in this setting,
so that
accounts for some of the new
prescriptions written
in our group, as well.
While the comment, and I
certainly agree
with most of what Dr. Temple said, I mean
we don't
82
have a winner here in the sense that
there is not
randomized data between erlotinib and
gefitinib to
date, so I think for many of us, the
direction of
this class is heading into what subsets
will
benefit, and for now we don't know direct
head to
head the differences in the two.
Certainly there are small
differences in
terms of mechanism of action,
pharmacology and
toxicity.
DR. MARTINO: Mrs. Ross, you will have the
last comment, and then I am going to turn
to the
public forum.
MRS. ROSS: Thank you very much, Madam
Chair.
I just had a quick question
actually for
Dr. Pazdur and Dr. Temple. You are not suggesting,
are you, that doctors should not be
allowed to
write new prescriptions for Iressa?
DR. TEMPLE: Well, no.
First of all, we
don't control what doctors write, but
there isn't
any doubt that--I don't know what you
mean by a new
prescription--a new prescription for
Iressa in
83
someone who is already on the drug and
responding
to it is not an issue.
MRS. ROSS: New patient new to the drug.
DR. TEMPLE: I am more worried about what
AstraZeneca is telling people. I thought it was
fairly clear they thought, given a
choice, for
someone who wants that mechanism, they
would use
the drug that actually showed a benefit,
not the
drug that didn't.
I no longer am clear that that
is their
goal after this presentation today. It sounds much
more ambiguous than that, and I am just
trying to
find out what it is. I thought the comment about
what is being done in Tennessee makes a
lot of
sense, if you think that therapy is
appropriate,
use the drug that won.
Look, we have been pushing, if
anything,
the idea that there are subsets of the
population
that are more likely to respond than
others, and
that has been I think apparent from the
earliest
data with Iressa. There undoubtedly are
differences among subsets of the
population.
But Ralph can comment on
this. All of
those differences in a trial are much
more credible
when the trial wins overall or when you
have
84
specified that as the primary
endpoint. It remains
somewhat after the fact, not implausible
given the
other data, that people who never smoked,
you know,
are much more likely to respond.
All those things are probably
true, but
still, given a choice of two drugs now,
one of
which has a quite successful overall
clinical
result, and the other of which doesn't,
most of the
time people would suggest that you use
the one that
actually had the favorable result.
I thought that was the
direction
AstraZeneca was urging people to go. I am not as
sure of that after hearing the
presentation today.
DR. SCOTT: Could I--
DR. MARTINO: I am sorry, I need to ask a
question here.
Has the FDA had the opportunity
to review
the materials that have been prepared by
AstraZeneca?
DR. TEMPLE: Yes.
DR. MARTINO: You have.
So, you have
seen, in fact, the written materials?
DR. PAZDUR: The written materials, yes.
DR. MARTINO: Okay.
And can I trust that
since they are in the public media now,
that, in
85
fact, you have agreed or approved, or in
some way
decided that they are okay with you? I
understand--
DR. TEMPLE: We did.
I am now slightly
nervous about them.
DR. MARTINO: I understand the concept of
what is their intent, however, I think
what we, as
a committee, can judge is the steps that
they have
taken, the material that they have
supplied, and
the
content, the written content in that material,
is it fair, appropriate, and informative.
What their intent might be in
their gut
and in their heart, in all fairness, I
think I
understand your question, but it is not
really what
this committee can deal with.
DR. D'AGOSTINO: Can I go to Bob's
86
question?
I mean I thought that what we were
looking at was basically this letter, and
that I
think is fine, and I think it reflects
what the
data shows.
I am bothered by the
presentation that
if--are they also, are they putting this
letter out
and then showing this presentation,
because the
presentation has a completely different
bent to it,
and my question was going to be, what is
their
presentation to the field, is it just
this letter,
or are they throwing this--now, that is
different
than the people who are running the
studies.
The ones who are running the
studies
obviously have to see this, but what is
the
collection of M.D.'s being told?
DR. MARTINO: That is an important
question, that, I would like the company
to answer
to.
DR. SCOTT: If I could respond first and
have Judy Ochs talk about the intent of
the letter.
Again, the intent of the letter in
December is the
intent today, and I will have Judy Ochs
talk about
87
the intent, please.
DR. OCHS: Yes, I did send the letter, and
my signature is on it, and I stand by
it. That was
the letter that we sent out. What we said in that
letter is true. It is no less true today.
The presentation today,
however, reflects
some time, now that we have the full
totality of
the data, we are beginning to look at it,
it will
be submitted to you. The FDA will review it.
Again, many times when one goes through
protocols
and through data, there will be the data,
there may
be some aspects to the interpretation.
The bottom line, that the trial
did not
meet statistical significance has not
changed.
DR. MARTINO: One more question and then I
will turn to the open forum, please.
DR. REAMAN: You did show data today about
a particular subgroup or subgroups that
do appear
to potentially have more of a benefit
than others,
the corollary being that there is a large
group
that don't appear to have any benefit.
Is that data that has only been
made
88
available to you since the letter went
out in
December, and, if not, why wasn't there
any mention
of that in the communication?
DR. OCHS: When the letter went out, that
is all we had. We didn't have the rest of the data
to a large degree. We hadn't had any opportunity
to look at it. We literally saw the data, about 10
people, on Tuesday, and the data went out
Friday
morning, it was that quick a happening.
Again, I think as we are
looking at the
data ourselves, it is clear. The one thing I would
say is that as Kevin presented in his
presentation,
all of the patients, if you look at the
hazard
ratios, it is to the left in terms of
potential
benefit for Iressa.
There obviously are, as Kevin
pointed out,
variability, but nonetheless, we are
looking at a
trial that barely missed reaching
statistical
significance, so it is not like there
wasn't
benefit, it did not meet a statistically
defined
endpoint to which we all agree, and to
which we
would not change our recommendation to
physicians
89
that solely based on the data, but I
think that Dr.
Kris and Dr. Burris have brought up other
things,
other data that is out there, other
information.
And I think one of the things
that has
happened is that Iressa has been around
for a
while, people have had some experience,
so people
will be looking at the literature. Certainly, the
first opportunity for the data as a whole
to be
seen is today.
We submitted it to a scientific
forum
where it will be presented. There will be
questions asked. It will be questioned, and it
will be submitted to peer-reviewed
journals.
Open Public Hearing
DR. MARTINO: Thank you.
We will continue
this in a few moments, but at this point
I do want
to turn to the open public hearing. There are
several of you that have asked to speak,
so the
microphone that you will be using is in
the center
of the room.
Allow me to read the following
in
anticipation of your presentations.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and
decisionmaking. To
90
ensure such transparency at the open
public hearing
session of the Advisory Committee
meeting, the FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages
you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
committee of any financial relationship
that you
may have with the sponsor, its products,
and, if
known, its direct competitors.
For example, this financial
information
may include the sponsor's payment of your
travel,
lodging, or other expenses in connection
with your
attendance at the meeting.
Likewise, the FDA encourages
you at the
beginning of your statement to advise the
committee
if you do not have any such financial
relationship.
If you choose not to address this issue
of
financial relationship at the beginning
of your
91
statement, it will not preclude you from
speaking.
Ms. Clifford, if you will
announce our
speakers, please.
MS. CLIFFORD: Peter Lurie is our first
speaker.
DR. LURIE: Good morning.
Peter Lurie
with Public Citizens Health Research
Group. I am a
physician. I have no conflicts of interest to
disclose.
We take no money from government or
industry.
As the members of the committee
will I
hope have noticed by now, this morning
Public
Citizen filed a petition with the FDA to
remove
Iressa from the market on the grounds
that no less
than three mortality studies have now
proved
negative.
We, instead, ask that for those
patients
who remain on the drug, and completing
courses of
therapy, that they can receive the drug
through IND
status.
You will notice, too, that in
Europe, the
marketing application for Iressa has been
withdrawn
92
and that in Japan, the Ministry is giving
serious
consideration to removing the drug from
the market.
As you all know, Subpart H is
the
mechanism through which this drug was
approved, and
to emphasize, that accelerated approval
law makes
clear that the FDA may withdraw approval
of a fast
track product "if a post-marketing
clinical study
fails to verify clinical benefit."
That is
certainly the case over here.
In fact, even prior to
approval, there
were a couple of studies that showed lack
of
clinical benefit, and the two instant
studies were,
in the words of the FDA medical officer,
"unambiguously negative," and
the medical officer
made the observation that "the FDA
has never
received a cancer drug application for
accelerated
approval when definitive data in another
related
setting showed a lack of efficacy."
Those were first line therapy trials,
which were both negative with respect to
mortality,
and the drug on the market for third line
therapy,
of course, we will acknowledge the
principle in
93
oncology is that a drug is most likely to
work as
first line therapy rather than third line
therapy,
and, of course, in the end, that is
exactly what
the ISEL has confirmed.
So, we have these two negative
mortality
studies even going into the approval of
this drug.
Now we have the ISEL study, which shows a
very
small survival difference, 27 versus 22
percent,
but not statistically significant under
the primary
data analysis.
As you will notice from the
slides
presented by AstraZeneca this morning,
the overall
quality of life was also not benefited by
Iressa.
Instead, what we have seen, you
have all
heard of rescue chemotherapy, I think what
we have
seen here is rescue biostatistics. A number of
subanalyses that have been done, some of
them
aren't clearly post-hoc, especially the
Asian one.
You will notice from your briefing
materials that
some subanalyses are described as
prespecified, but
the second table is one that implicitly
are not
prespecified. The Asian group is among
them.
How many of these subanalyses
have been
done?
Why is it that the rather simple to conduct
multivariate analysis has not been done,
and why is
94
it that conveniently none of them are
ready for
this meeting?
In response, we have seen the FDA
put out
a letter.
We have seen another letter from
AstraZeneca, which in effect are telling
patients
to think about not to take the drug. I mean what
kind of public health approach is this to
have a
letter from a drug company that, in
effect,
suggests that patients not take their
drug?
That doesn't seem like an
adequate public
health response to us, and, in fact,
patients are
still taking the drug, 331 new
prescriptions in the
week of February 18th. The company may
claim that
these are not new patients, but there is
no
evidence for that either.
The fact is that there is a
drug on the
market which has clear, proven mortality
benefit,
and patients can easily be diverted from
the
effective therapy to this one for which
there is no
95
benefit.
As Dr. Temple said, if there
are two drugs
that are available, why not use the one
that won.
There are also dangers from
this drug, and
we have outlined these in prior letters
to FDA,
particularly in the area of interstitial
lung
disease, 588 deaths now in Japan, and our
analysis
of the adverse drug reaction data from
FDA show 144
reports of interstitial lung disease
including 87
deaths in this country just since the
time that the
drug was approved.
What really we are seeing over
here is an
elaborate dragging out of this process, a
drug that
probably should not have been approved in
the first
place, and now, even while empowered by
Subpart H
to remove the drug from the market, it
still hasn't
happened.
How ironic this is. A company gets a drug
on the market through an accelerated
approval
process and then when the data turn out
to be
negative, suddenly it goes slow - let's
wait for
the EGFR data, let's wait for the
easy-to-do
96
multivariate analysis that we haven't
done, and the
EGFR data will be ready, would you believe
it, in
two to three weeks from now, it couldn't
be ready
in time for this meeting.
These EGFR analyses should be
thought
about in the following context. In the Phase II
trial, there was no relationship between
the
expression of EGFR and outcomes. There is
no
calculation of a positive predictive
value for
these mutations.
Clearly, people without them
are
responding and vice versa. We really don't know
the positive predictive value, and as was
also
pointed out, this is a research
tool. It is not
something--and even AstraZeneca admits
this--that
can be used to distinguish patients at
present, and
therefore, decide whether or not to
provide them
with therapy.
If this is important enough a
question, it
should be researched, and the IND is the
appropriate mechanism to do that.
Finally, to close, with Subpart
H, if ever
97
there was a drug that was slated for and
eligible
for removal from the market under Subpart
H, this
is it, a drug, which even for the
indirect--sorry--for the surrogate marker
had
minimal benefit in the Phase II
uncontrolled,
non-placebo-controlled, even unblinded
trial,
minimal benefit on the surrogate markers,
clear
dangers, proven effective therapy in
terms of
reducing mortality, and now patients
continue to be
placed on the drug, and three negative
mortality
studies.
If this drug is not taken off
the market
on these grounds, it will make an
absolutely
mockery of Subpart H.
Thank you.
MS. CLIFFORD: Thank you, Mr. Lurie.
Our next speaker is Laurie
Fenton.
MS. FENTON: Good morning.
I am Laurie
Fenton and I am President of The Lung
Cancer
Alliance, the only national organization
that is
dedicated exclusively to advocating on
behalf of
lung cancer patients and their caregivers
and
98
survivors.
DR. PERRY: We can't hear you very well.
MS. FENTON: Okay.
How is that?
Again, Laurie Fenton, the
President of The
Lung Cancer Alliance. We are the only national
organization that is dedicated
exclusively to
advocating on behalf of lung cancer
patients, their
caregivers and survivors.
I believe you have my
statement, so I will
condense what I would like to present
today.
AstraZeneca has provided grants
in the
past for educational programs, but they
have not
compensated me in any way today to
present what we
are here to share.
The Lung Cancer Alliance
understands that
the FDA is required by statute to
evaluate drugs by
looking at safety and efficacy data in large
populations of patients to determine
whether
benefits outweigh the risks.
Interestingly, we have
discovered that
Iressa does not fit neatly into this
protocol, and
while Iressa's current clinical trial
data has not
99
revealed dramatic survival benefits
overall, it has
shown striking benefits for a small
subset of the
larger population, with less side effects
and
quicker response rates.
As was shared earlier, we
received many
phone calls from patients who were
extremely
concerned that Iressa could be pulled
from the
market, particularly a drug that had
helped them so
dramatically.
Patients spoke of stockpiling
the drug and
beginning to take Iressa every other day
to make
their supply last longer, and I am glad
you will be
able to hear from patients directly on
this point.
The reality is that we have an
unmet
public health need. Lung cancer's mortality
statistics can no longer be ignored. Beyond
demanding that government redirect its
own
resources to effect change, we as
advocates also
want to nurture responsible drug
development to
help in our fight to eradicate this
number one
cancer killer.
Alimta and Tarceva, recently
approved for
100
the treatment of lung cancer, are
important arrows
in our treatment quiver, but Iressa must
also be
recognized as an important weapon in this
battle.
Even if unable to meet the broad
population standard, we cannot ignore the
fact that
Iressa has shown striking benefits within
a subset
of the population, and to this effect,
lung cancer
patients and their doctors need all, not
limited,
choices now.
It is our hope that both the
FDA and
AstraZeneca find a way to allow doctors
and lung
cancer patients access to Iressa while,
at the same
time, agreeing upon a way to further
study and
evaluate the drug.
It could provide a window of
opportunity
to better understand the horrible disease
that lung
cancer is, who will benefit most from the
drug
treatments and why.
I again thank you for allowing
us to be
represented here today.
MS. CLIFFORD: Thank you for your
comments, Ms. Fenton.
Our next speaker is Selma
Schimmel.
MS. SCHIMMEL: Good morning.
My name is
Selma Schimmel. I am the CEO and founder of Vital
101
Options International. It is a nonprofit cancer
communications and advocacy organization
that also
produces the Group Room Cancer talk radio
show,
which weekly gives me an opportunity to
speak with
a great many cancer patients.
While I am not a lung cancer
survivor, I
have survived both breast and ovarian
cancer. I
want to clarify that I have no financial
interest,
investment, or gain associated with my
presence
here today, but I am here to help lung
cancer
patients, their loved ones dealing with
non-small
cell lung cancer, and because I really
believe that
we are at a crossroads and a convergence
of
technology that necessitates a new
dialogue and
opportunity for positive change.
Patients and medical consumers
deserve
choice, but most importantly, they need
and expect
full disclosure and rational explanations
to help
them make informed choices, and what
patients
102
especially need are adequate safeguards
to protect
them from erroneous choice.
As advocates, we thank and rely
upon our
partners at the FDA and the NCI. We also applaud
AstraZeneca's prompt and open disclosure
regarding
its top line Iressa data results on
December 17th,
2004.
It was a respected and valued action and of
particular importance at a time when the
general
public has such a lack of trust and
expresses
hostility towards the pharmaceutical
industry and
the regulatory and approval process.
So, I bring a question to the forefront,
because it is really at the core of
today's
proceedings, and because the process and
the course
of action being taken now sets a tone and
a
precedent for our future.
How am I to respond to the man who tells
me that he has read that Iressa has no
survival
advantage, that it is not being used in
Europe, yet
he will begin receiving it here? I find I have no
reasonable and satisfactory answer.
But what the patient is really
asking is
103
how many patients are being harmed by not
receiving
the most effective and safest product for
their
disease.
How can patients advocate for themselves
when they are receiving conflicting
information and
double messages?
Finally, how can patients trust
the
system?
While Iressa should remain available to a
defined patient population who might
benefit, as
well as for the subset of patients who
are already
responding favorably or for whom there is
no other
option, a labeling change is needed now,
not months
from now, to reflect the current indications
and
information, so patients are not
mistakenly
deprived of their best treatment option
and to
avoid further patient confusion and
misperceptions,
a labeling change allows for the full
circle of
information disclosure to be complete, as
well as
implemented.
Iressa has paved the way for a
deeper
understanding of the differences between
EGFR
agents.
There is much yet to be understood about
Iressa and the scope of who may and may
not
104
benefit, as well as which patient groups
may derive
comparable or perhaps even greater
benefit from
Iressa than other proven therapies.
One of the great hopes is the development
of proper screening assays, but since
none have
been scientifically validated, patients
are in need
of additional security and safeguards.
So, as we face a new world in
medical
technology, we must also try to bridge
the
communication and comprehension gap
between
patients and providers. It is hoped the decisions
coming out of this meeting are made in
context to
today's fragmented medical culture and
evaluated in
its entirety for the much broader and
significant
implications that will impact the
oncology
community in general, color public
perception and
attitudes associated with clinical
trials,
confidence when trials are negative or
halted
early, and drugs that are developed under
an FDA
fast track application.
Advancing and widening
technology requires
a mechanism to teach the public and to
instill
105
trust.
Thank you very much. I have copies of my
statement at request.
MS. CLIFFORD: Thank you, Ms. Schimmel.
Our next speaker is Rosalind
Brannigan.
MS. BRANNIGAN: Good morning.
My name is
Rosalind Brannigan and I have no
financial
relationship with AstraZeneca except that
I am
buying its drug.
Recently I have had two
profound shocks.
First, in November of 2003, I
broke my arm
at my health club and was diagnosed with
Stage IV
non-small cell lung cancer. This was a major shock
to someone who had not smoked in 38
years, who
exercised an hour a day, and who has
spent their
life working in public health.
I underwent six months of
weekly
chemotherapy, platinum and Taxotere. Three months
later, my cancer had come back and had
metastasized
to my liver, and I was put back on weekly
chemotherapy.
Shortly after that, I learned
from the
106
Massachusetts General Hospital that I had
the
genetic mutation to be a candidate for
Iressa, and
I was put on Iressa in October of 2004.
By December, when I had a PET
and CT scan,
it showed that my tumor in my lung and my
liver had
both reduced significantly in size and
that my CEA
tumor marker had plummeted by 90 percent.
However, this good news was
immediately
followed by having me open the New York
Times on
December 20th and to read that FDA was
reviewing
its approval of Iressa and that it might
take this
drug off the market.
Just last Friday I had another
PET/CT
scan, and it showed that the tumors in my
liver are
completely gone, and that the tumor in my
lung
continues to shrink.
Iressa is working for me. When I asked my
oncologist if I should switch to Tarceva,
he said,
"Absolutely not." He was adamant that I stay on
Iressa because it's working for me, and
he thinks
it's a wonderful drug for all of his
patients in
his practice who are responding to the
drug.
Iressa should remain available.
Thank you very much.
MS. CLIFFORD: Thank you, Ms. Brannigan.
107
DR. MARTINO: Thank you, ladies and
gentlemen.
Committee Discussion
We will now return to the
committee's
proceedings in terms of if there are
additional
questions, but as I let you do that, let me read
for you the questions that I really want
you to
discuss and to think about.
1. Discuss whether the content of the
information communicated by the FDA and
AstraZeneca
on Iressa is satisfactory. Should any other
information be communicated?
2. Further, discuss whether the target
audience and the selected means of
communication
are satisfactory. Should any other
audiences or
means of communication be used?
Now, in your packet, you each
have a
letter from the FDA, and there is also
the Dear
Doctor letter that AstraZeneca has
provided. What
108
I, myself, have not seen is what has been
provided
to the lay public. It sounds like there has been
information provided in various
magazines, et
cetera.
Can someone from the company
review that
for us and tell us what the content of
that
information is, because providing
information to
physicians is critical, but with this
drug I am
concerned that unless we communicate
properly to
the lay population, we may be confusing
them rather
than helping them as I think our last
speaker made
clear to us.
DR. SCOTT: I will ask Carolyn Fitzsimons
to come and talk about the patient
communications.
MS. FITZSIMONS: Thank you.
Can I just
clarify the question you are asking, you
want to
know about the content of the
communications
directly to patients and the public?
DR. MARTINO: Correct.
MS. FITZSIMONS: On December the 17th, as
was shown on the original presentation by
Dr. Ochs,
we immediately informed the patient
advocate
109
groups.
We had a teleconference with them, gave
them the information about the top line
results
with the guidance that should they have
any
concerns, that they should go at their
first
opportunity to consult with their
physicians about
what the most appropriate treatment
options would
be.
We did say that they should not
stop
taking their Iressa until they had spoken
to their
physicians and deemed what was the most
appropriate
action in consultation with their
physicians.
We also put out similar
information on the
AstraZeneca website and also on the
specific Iressa
websites also.
Subsequent to December 17th, we
then went
back to our own records where we had got
information from patients who had
contacted
AstraZeneca directly to gain information
about
Iressa or were on our patient assistance
program
for Iressa.
So, any known patients to
AstraZeneca, we
went out a mailing, either postal or on
e-mail to
110
inform them of the information, provide
them with
the Dear Doctor letter, and give them the
guidance
that at the first opportunity, they
should consult
with their physicians about their ongoing
treatments and what would be the best
choices for
them.
DR. MARTINO: Has the FDA seen any of the
written material for the public, and are
you
satisfied with it? Is that a yes or a no?
DR. PAZDUR: Yes.
DR. MARTINO: Generally yes? Okay.
Dr. Hussain, you had a
question?
DR. HUSSAIN: I want to thank the members
of the public that presented, and I
thought that
their comments were very thoughtful, to
be honest
with you.
It kind of encapsulated everything that
this committee is facing at this moment.
But I want to go back to the
presentation
that Ms. Schimmel had done and Ms.
Brannigan.
Before coming here I talked to my lung
colleagues
who deal with lung cancer and have worked
with
Iressa and Tarceva, and a variety of
other agents.
111
I have myself not used it in the setting
of lung
cancer.
What I was impressed by is
their
impression from their own patients that
there is
clearly subsets of patients that benefit,
and I
think Ms. Brannigan is a perfect example
of that.
So, there is no question as doctors,
ethically, it
is going to be very hard to say to a
patient who is
on it and is responding, or is likely to
respond
when there is nothing else that you can't
get it.
That, to me, doesn't make a lot of sense.
On the other hand, I think it
is also
unethical to keep it available for people
who we
know are not likely to benefit and to
allow that
part to happen, because there is an
ethical issue
of side effects and cost, and these
things are not
cheap, and there may be, by giving them
something
of this sort, will take them away from
stuff that
works.
I have to get back to the clinicians
in
the group, and I do agree with Dr.
Temple, when you
are starting a new patient and you have
two drugs,
112
one that stood the test, and the other
one did not
stand the test, to me, it, from a
clinical sense,
doesn't make sense to use a drug that
didn't stand
the test when you are starting a new
patient, but
that is where the art of medicine comes
in, and I
am not sure that I could argue that way
too much.
So, my point is to go back to
Ms.
Schimmel's recommendation, which I think
the
package insert and the labeling has to
change,
reflecting the fact that the definitive
trial did
not work, and that perhaps--and I don't
know if
that is allowed--that there are some
subsets that
seem to benefit, and that if one is to
use the
drug, perhaps they could consider using
them in
that subset to give some guidance to the
physicians.
The other thing, to the
patients, I think
that considering that industry uses the
media to
advertise their drugs, perhaps to ensure
that every
patient had heard about it, is to use the
media to
indirectly say something, so that they
can contact
their doctors as another means of
assuring that
113
people have heard about it.
The other concern I had, had to do with
the labeling of people as Asian. We live in the
United States and have certain definition
of
ethnicity, which I am not sure that are
clear. I,
myself, was born in Baghdad. I consider myself
Asian.
So, does that drug apply to me?
I think when we talk about
benefits in
general, and I wouldn't consider a
Japanese person
equal to Vietnamese, equal to Chinese,
equal to
Indian, Pakistan, Afghanistan, and
on. I think
those populations have to be very clearly
defined
beyond this Asian ethnicity thing,
because I don't
really know what it means.
DR. TEMPLE: It's actually, I mean I am
not saying this is fully worked out, it's
actually
non-Caucasian who seem to do best. It is not
entirely--it was actually some mixture of
Japanese,
some mixture of other people, but
non-Caucasian was
the subgroup.
DR. HUSSAIN: I think we get wrapped up in
these ethnicity race issues. To be honest with
114
you, I don't even know what I would even
describe
myself, so we have to be very clear about
those
definitions.
DR. TEMPLE: You are right, and it is
totally after the fact, and I doubt if
you probed,
you would always get a good answer on who
it was.
I do want to remind everybody that the same
subsets
that seemed to be responding better here
are the
same subsets that respond better to
Tarceva, too,
except there you have some EGFR data that
helps
shed light on it.
DR. PAZDUR: Perhaps that's an area that I
would like to focus on in the discussion
and get
several people's opinion on, in this fact
of new
patients, and that is what we feel very
uncomfortable with here, basically, what
should be
the option for new patients that would be
looking
at an EGFR receptor drug.
Here again, you have two drugs
here, very
similar, similar response rates, similar
facts,
that if you take a look at their
development
program, they have had failed trials in
first line
115
settings when combined with chemotherapy,
however,
in the Registration study for Tarceva,
there was a
survival advantage seen and secondary
endpoints
were positive in this trial, so we are
quite
comfortable that that was a win for this
drug.
Given the information, given
the fact that
there are similar subsets also that we
see in the
patients between Iressa and Tarceva, and
remember
the Iressa data is somewhat subject to
questions
about these subsets, because they did not
win on
their primary endpoint, so looking at
these subsets
could be statistically ambiguous or criticized.
Given that fact, given a new
patient, what
should be the treatment option if you are
looking
at a EGFR receptor drug?
DR. MARTINO: I am having a hard time with
all of this, Rick, which is we are now
getting to
issues of as a physician in my own
office, okay,
how do I practice medicine, and I
practice medicine
based on everything that I know at that
moment, so
any of you, be it the drug company, be it
the FDA,
be it anyone, the only thing that you can
do is
116
provide me the opportunity for me to know
something. That is all you can do for me.
You cannot be in a position
where you are
looking over my shoulder saying, but, Dr.
Martino,
did you actually consider that your
patient was
male or female, that they were Asian,
whatever in
the hell--excuse me--that means. That is
not the
position that I think either of you can
take.
The issue at hand, as I think I
understand
it, is have both sides communicated that
there is a
problem with this drug, and that people
have to
recognize that there are alternatives,
the
alternatives are not unknown, so it is
not for you
to do anything more than I think to make
people
aware, that you are reminding them that
there are
alternatives, and that you are reminding
them that
they have to think.
I kind of have the feeling like
now we are
moving into, you know, how do you sit in
my office
and look over my shoulder. I don't mean to be
unkind, but that is what I am sensing
here, and I
don't know that any of you can do that on
either
117
side of this table.
DR. TEMPLE: There is labeling that, for
one reason or another, sometimes suggests
that
another drug be used before this
drug. There is a
calcium channel blocker called deprenyl
that has
pronounced effects on the Q-T
interval. It is
recommended for people who don't respond
to other
calcium channel blockers for angina.
So, labeling can do that if
there is a
good case for it. This isn't done lightly, of
course.
That doesn't force the doctor to do that,
it encourages them, shall we say. Clozapine, a
granulocytosis-causing antipsychotic drug
is
explicitly second line therapy because it
is
thought that you should fail first on
something
that doesn't have that liability.
So, there are examples of that
if that is
appropriate. I should emphasize we don't do that
lightly because, you know, you are not in
the
office, you don't know the exact
circumstances,
that is fair, but sometimes you can
conclude, and
the sponsor concludes with us, that the
right
118
recommendation is this should be reserved
for
someone who fails on the other one, or
you should
try that one first.
That is something labeling does
sometimes
say.
DR. MARTINO: But that is an issue whether
you are ready now to change the labeling,
and I
don't know that that is again the
discussion from
today's meeting. I appreciate you have that
responsibility.
Who is next on my list
here? Dr.
Mortimer.
DR. MORTIMER: I think the issue from an
evidence-based standpoint, in answer to
the FDA, is
clearly that the data support the use of
erlotinib
as
first line therapy.
I think where the gray zone
happens is a
statistical one, and what do we do when
there are
overlapping confidence limits, when the
difference
in response is 8 and 9 percent, but the
confidence
limits overlap.
I think the third issue that is
concerning
119
that we don't know the answer to until
crossover
data is available, is are the same patients
responding to Tarceva, the same patients
that
respond to erlotinib, and I guess we
don't know
that yet.
So, the statistical question I think is
at the heart of this.
DR. D'AGOSTINO: I guess I just didn't
think we were going to be talking statistics, I
thought we were going to be talking what
is the
material that is being presented, and I
am very
concerned that we have an accelerated
approval
product here, it has been approved, and
you can't
ask the sponsor to sit on the data, and
not get it
out in the literature.
So, what I am concerned about
is that I
think these letters are fine, and I
understand the
letters for the public seems to be fine,
but if
tomorrow we go to professional meetings
and we
start hearing a lot about these subsets,
then, I
think there is going to be an awful lot
of
confusion.
So, maybe we need an
accelerated review of
120
this material, so that we can have the
statistics
question, because again I did not come
here
thinking we were going to have a
statistics review,
but rather is the public being made aware
of the
fact that the study was negative on the
overall,
and then what else might be needed, and I
think
what needs to be needed is a quick review
of the
actual data, so we can answer your
question.
DR. MARTINO: Dr. Proschan.
DR. PROSCHAN: I think the statistical
issues, it is not clear cut. I mean this trial
really is about as close to being a
positive one as
you can get in the sense that if they had
used a
Cox model, which people feel is fine, you
know,
they would have gotten a significant
effect, so it
is not just the subgroups, it's other
issues as
well.
I had problems with some of the
presentation. In particular, the graph showing the
comparison of Iressa to docetaxel, you
know, and
the claim that, well, we are not seeing
much of a
difference there, and we would have if it
were a
121
placebo.
I have a problem with that.
That is a small sample size and
I am not
convinced at all that there is not a
difference
there that would be seen with a larger
sample size.
So,
I have problems with some of the presentation
this morning, but it is very thorny.
I disagree with the
classification that
this is a negative trial. There is negative and
there is negative. This is a negative trial, but
there are extenuating circumstances, as
well.
DR. D'AGOSTINO: But, again, we don't
really want to get into this, but the Cox
analysis
has some assumptions carry to it. These curves are
sticking together and then they separate,
so the
assumption may not be met of
proportionality, and I
am not going to say another word about
statistics.
[Laughter.]
DR. MARTINO: Thank you.
Dr. Perry.
DR. PERRY: I would like to point out that
during the brief time I have been on the
committee,
the FDA has approved several drugs
without my help,
and I am sure they have also turned down
several
122
without my help, so it seems to me that
the only
things that come before this committee
are those
that are bathed in shades of gray.
So, I think it is clear that we
have
varying viewpoints, that we have very
different
interpretations of the evidence before
us, and I
expect that is why we are here, and so I
don't
expect that we are going to walk away
with a clear
black or white decision.
When I raised my hand half an
hour ago, I
was trying to address--
DR. MARTINO: I do apologize.
DR. PERRY: Yes, I understand. You are
doing a wonderful job in a difficult
circumstance,
particularly when all of us love to hear
our own
voices, they resonate so well.
I was going to address Question
No. 2,
which is whether target audiences have
been
addressed selectively. I have to say, to give
credit to AstraZeneca, I have got more
notice about
this drug than I have credit card
applications, so
they have clearly done a good job in
saturating the
123
medical community, at least the lung
cancer
doctors.
I can't speak to the lay
public, but they
have clearly I think gone over and above
their
obligation to communicate with
doctors. I can't
think of another time in which, in my
practice, I
have been so inundated with information
about the
adverse effects of a drug.
DR. MARTINO: I do apologize officially
and personally, and thank you.
Dr. Brawley.
DR. BRAWLEY: Run down your list, Madam
Chairman. My first thought is I must say
to the
advocates I appreciate all four of their
comments
this morning, because so
frequently--well, let's
just leave it that I got something
positive and
something to think about from every
advocate's
statement this morning.
I wonder why so many patients
were
concerned that Iressa might be pulled,
and was
there some press, did anyone do something
to
frighten patients into believing that
this drug
124
that they are on is going to be pulled
away from
them.
Next, going into Questions 3
and 4, and
actually addressing the advocates and the
survivors, I think we all owe them an
apology
because the development of this drug has
been
mishandled. It has been mishandled by AstraZeneca,
it has been mishandled by this committee.
I, myself, take some blame for
that,
because I voted for approval of it two
years ago.
The fact remains that this drug has been
available
for 7 years, and we still haven't figured
out
exactly how this drug should be used in
the
treatment of lung cancer.
Perhaps if we had held off in
getting it
available to people two, three years ago,
those
studies would have been done. There are a number
of studies that have done a number of
subset
analysis, and I have made my career, by
the way, by
saying we should not do subset analysis
based on
race, because race or ethnicity is not a
biological
categorization of populations, it's
non-scientific.
I actually think I was quoted
in the press
when I voted for this drug two years ago
saying
that this is lung cancer's tamoxifen in
search of
125
its estrogen receptor. Unfortunately, the failure
to totally find and totally categorize
that
estrogen receptor is the reason why we
are in the
pickle that we are in today.
It may very well be that
people--Asian is
a way of racial profiling, and the best
way to
politically--I am sorry--the best way to
scientifically profile is people who
happen to have
that receptor, which may very well be of
a higher
prevalence in people who were originally
born in
Japan or China, or maybe even Iraq.
That is what we have got to
start doing,
and we have got to be much more
scientific. Now,
in partial defense of everybody who
mishandled the
development of this drug, including
myself, this is
one of the first of the targeted
therapies to come
along, and none of us really had
developed target
therapies a lot before this one came
along, so we
need to learn from our mistakes and go
forward.
With that, I will relinquish
the
microphone.
DR. MARTINO: Dr. Levine.
DR. LEVINE: Several comments. First, I
will agree, I mean there is not winning
and not
winning, and this is on the edge, and I
don't
126
honestly believe in my soul that there is
no
efficacy of this drug. I think the company have
shown data to suggest that there may be
something
there.
The other thing that bothers me
a little,
I wasn't on the committee either for
Tarceva or
Iressa, and I don't know the data, but we
are
hearing or I am hearing that Tarceva is a
"better"
drug.
So, my question is, by chance,
how many
women were on that trial, how many
non-Caucasians,
how many non-smokers, and I don't know if
it is
fair to compare one drug to another when
those very
important issues have not been presented
to us, and
I know we aren't asked to do that, but
that is a
comment I have. I feel disquiet about it.
The second is an administrative
question.
The company was asked, after accelerated
approval,
to do three studies. One study was agreed upon
that should be dropped, but my question
to the FDA
is, if you are going to base everything
on one
study out of two, why were they asked to
do two or
three, and what is the administrative
concept here,
if the company is asked to do two or
three studies,
aren't we, in fact, obligated to look at
all of
127
them in making our decisions.
That's it.
DR. MARTINO: Dr. Temple, Rick, you want
to comment on that?
DR. TEMPLE: Rick has to remind me what
the second study is, but I think the
short answer
is this was a very large study. You would expect
it to be able to detect an overall
survival effect
if there was one, and the fact that it
didn't tells
you something.
It absolutely, as people have
said, it
doesn't prove the negative. A negative study never
proves the negative almost. Maybe if it's
128
significantly worse than no treatment,
but that
hardly ever happens, but it doesn't
support the
positive.
Not to get too far apart, but
we are
learning in more and more cases that
there are
subsets of the overall population that
respond, and
if the subset is too small, you will not
have an
overall effect on survival, that is
inevitable.
That doesn't mean the drug is useless.
So, there are obviously people
who respond
dramatically, and if you could identify
them ahead
of time, you might be able to show there
is a
survival benefit in that subset we were sort
of
talking about this yesterday, but this is
a
developing area and we don't yet quite
know how to
do that.
Just for what it's worth, in
the Tarceva
data, there are some very intriguing
things. For
example, if you look at the subsets of
people who
do particularly well, like nonsmokers,
it's the
nonsmokers who are EGFR-positive who do
spectacularly well, it's not the
nonsmokers who are
129
EGFR-negative who do spectacularly well,
and that
is true for women and all those subsets.
So, you know, we are not
declaring any of
that definitive, the number of patients
in the
negative subsets are too small to be
definitive,
and the confidence intervals overlap, but
you are
starting to get the impression that these
data are
telling you something, but it is still
early.
But one of my problems with survival
data
in general is that if the response rate
is low
enough, you can't bring the whole study
along
unless you have a population of a million
or
something, and that doesn't mean it
doesn't work,
so we have got to get better at
identifying who the
potential responders are, so you can
study them and
identify them as the people to be
responders.
Anyway, the new study even
without the
additional study, gives you more
information than
you had before, and I think the view
would
generally be that that should be
reflected in
labeling, and if you learn something else
in
addition, you add that.
DR. PAZDUR: We generally do ask for other
than just one confirmatory trial. We are
interested for the development of the
drug, and we
130
are realistic that a trial can fail, in
quotes, by
chance alone obviously.
Given the fact there are other
trials, the
docetaxel trial, it was a difficult
trial, and we
brought this same question to the
committee several
months ago when we looked at Alimta.
One cannot do a non-inferiority
trial
here, they have to beat this drug. A
non-inferiority is impossible to do in
this setting
and we had lengthy discussions, which I
won't bore
you with, on this whole issue of
non-inferiority
with docetaxel.
But there are problems here,
and that was
specifically stated by us, had to be a
superiority
trial. This is a placebo-controlled
trial. It is
about as clean as you could get here, and
obviously, this is bothersome or we
wouldn't be
here to bring this to people's attention.
DR. MARTINO: Mrs. Ross.
MRS. ROSS: Thank you, Madam Chair.
First, just an administrative
technical
question and then one other
question. I didn't
hear properly the start of the testimony
of Ralph
Nader's group. Did they file a financial
disclaimer on this, or were they
testifying on
131
behalf of someone?
DR. TEMPLE: He stated that he had no
conflict.
MR. LURIE: I made it perfectly clear that
we have no conflict of interest
whatsoever. We
take no money from AstraZeneca or any
other drug
company, or any other corporation, nor
from the
government.
MRS. ROSS: Thank you.
I just wanted to
clarify, I didn't hear that.
To Dr. Brawley's comments, I
was in the
audience the day you voted in favor of
accelerated
approval, and frankly, I am so glad you
did. I
know that Dr. Pazdur was not in favor,
and other
members from FDA, however--
DR. PAZDUR: You don't know that, you do
132
not know that, ma'am, you are not a mind
reader.
MRS. ROSS: In any event, it was approved,
we don't erase that, but I think we have
to look at
the benefits that have come from
this. First of
all, and let's not forget this, there are
a
significant number of people who have, in
fact,
benefited from Iressa. Their quality of life, as
the study done by Dr. Joan Shold [ph] at
the
University of Wisconsin, was greatly
improved.
Now, they might not be living
five years
out, we don't even know that. I don't even know
what the data is from Japan on longer
term survival
with Iressa, but the fact is that there
are people
surviving.
Secondly, the other enormous
benefit to
come from this is that it is focusing
attention,
large populations, on these targeted
therapies, and
who knows, maybe Iressa in combination
with a VEGF,
or in combination with something else,
might be the
real answer to a lot of these
recalcitrant late
stage lung cancer, but please, please
keep in mind
it has opened, like Laurie says, it has
opened a
133
window, we have another place to go to
look and
help these late stage lung cancer
patients.
Late stage lung cancer patients
only have
a 5 percent chance of survival. We can't cut down
on what is available to them to survive,
and it is
not just that it is not fair. I wholly agree with
you that we need to do more research on
these
receptors, in determining who will
respond to these
drugs, and we will do anything we can to
support
that research.
Perhaps if this committee makes
a clamor
for that, we might get the attention of
other
government agencies who are charged with
that
research and get them talking, too.
DR. MARTINO: Ladies and gentlemen, this
meeting is coming to a close. I need to remind the
group that you have gotten off track
here. Okay?
Even though I keep reminding you, the
point today
is not whether this drug dies or lives,
that is not
the issue here, and some of you refuse to
understand that.
The issue here was have we
sufficiently
134
informed the necessary people. So, I realize there
is no vote to be taken, but I, for my own
satisfaction, would like to hear an
answer to that
question, and I am going to start with
Dr.
Doroshow.
Are you satisfied that the public and
the physicians have been appropriately
informed or
not?
DR. DOROSHOW: Yes.
DR. BRAWLEY: No.
DR. D'AGOSTINO: Yes, but I am concerned
that we have to move, the FDA, the
sponsor has to
move quickly on making a resolution about
this
particular study, but I think they are
informed.
DR. PROSCHAN: Yes.
DR. GRILLO-LOPEZ: I don't have a vote,
but I do have an opinion, and I would say
yes,
because as a physician, I have been
receiving the
same number of communications by e-mail,
letters,
et cetera, that Dr. Perry has.
DR. MORTIMER: Yes, on the basis of the
e-mails and mail.
DR. PERRY: Yes.
DR. HUSSAIN: Yes.
DR. MARTINO: Yes.
DR. REAMAN: I will give a conditional yes
135
for the constituency of the medical
community, but
I don't think we have actually seen
anything that
has gone to the public, so I don't know
how we can
be asked to comment or vote on something
that we
have never seen.
DR. MARTINO: I actually think that is a
very fair statement. I mean we have been told that
the FDA has seen what has been put in the
public
media, and it is to their satisfaction,
so I guess
right now we have to kind of trust that.
DR. BRAWLEY: Madam Chairman--
DR. PAZDUR: We have examples in your
packet of the letter and their ad.
DR. REAMAN: The only thing I have in my
packet is a copy of the Dear Doctor
letter.
DR. WILLIAMS: But I do think we
should
mention it has been limited, I believe,
to the
patients AstraZeneca has access to, which
represents a subset, and I don't know if
there is
136
another way to reach those others. Certainly, the
advocates have been helpful.
DR. REAMAN: We heard that there is
announcements on websites. We have not seen that,
we could have seen that, that could have
been
provided, and it wasn't.
DR. BRAWLEY: Madam Chairman, the basis of
my no vote is I do think the physicians
have been
well informed, but I am concerned when I
hear
advocates say they are afraid that they
are going
to run out of their drug, and it is going
to be
taken away from them while they are on
therapy.
DR. RODRIGUEZ: I concur with the
previously stated comments. I actually don't know
what the public has heard. Obviously, the public
heard some negative statements from the
press,
otherwise, there would not have been this
fear in
the patients about the drug being
removed, which
isn't even an issue at this stage, as I
understand.
DR. MARTINO: Perhaps we can infer the
very fact that the public was so
concerned that the
drug is coming off of the market, that,
in fact,
137
the word that the results are negative
must have
gotten out.
That really is the issue here,
isn't it?
For them to be worried, that is the
message that
they heard, however they heard it.
DR. LEVINE:
I agree that the medical
community has been well informed, and I
am
respectful for the company of having done
a very
good job in that regard, but I am unclear
as to
what the committee is asking them to do
as far as
the patient community.
I don't think we are saying
that they
should be going out there and saying
don't worry,
this is all wonderful, the drug is
available. We
can't go in that direction.
I would be in favor of a label
change, and
I would also say to the company, in all
fairness,
and I don't know whether they did, if the
company
has directly advertised to the community
of
patients on TV and radio, they should be
asked to
directly advertise that the drug has
difficulties
here.
If they have not done that, then, fine.
MS. HAYLOCK: I am an oncology nurse and a
member of the Oncology Nursing Society,
and I would
just like to add that the Oncology
Nursing Society
138
was involved in distribution of
information, and we
have a membership of over 30,000 nurses.
So, I think the nursing community,
and for
those of you who have been through
treatment, I
think you realize that the oncology
nurses are the
ones who are oftentimes involved in
informed
consent and also patient and family
information,
and teaching, and for caregivers, as
well.
So, I think the nursing
community was also
involved in the dissemination of
information to
recipients and patients and caregivers.
DR. PAZDUR: In fact, the e-mail that we
sent out to ASCO simultaneously goes out to
ONS
membership, as well as is put on the NCI
website.
MRS. ROSS: Yes, we are quite satisfied
with the information disseminated to the
patients
and particularly in the follow-up, as I
mentioned
before, we did speak with FDA regarding
the calls
we were getting, and Dr. Pazdur was very
helpful in
139
crafting a statement that we could put on
our
website that would allay people's fears.
Their main concern was they
were afraid
the drug was going to be pulled
immediately, and
that came about because of the press and
certain
other citizens organizations that were
crying wolf.
Also, there is a vast network,
an on-line
e-mail list among patients, sub rosa, so
to speak,
and we, at the Lung Cancer Alliance,
immediately
notified every other lung cancer group we
knew plus
got Dr. Pazdur's statement up on those
e-mail
lists, so I think it was a very
widespread net.
DR. MARTINO: Last question from me to Dr.
Temple and Dr. Pazdur, at this point, are
you
considering revising the package insert,
or where
are you in that process?
DR. PAZDUR: Yes, we will be discussing
that internally.
DR. MARTINO: Ladies and gentlemen, that
is the end of this morning's
meeting. There is a
second topic and I am going to ask you to
return
here at 20 to 11:00, please, to start the
second
140
part of this meeting.
[Break.]
141
Call to Order and
Introductions
DR. MARTINO: Good morning, ladies and
gentlemen.
The topic for this morning's
meeting and
discussion relates to a safety concern
with the
agents Aredia and Zometa, specifically
osteonecrosis of the jaw.
Before we start into the topic,
I would
like the committee members, as well as
the members
from the FDA, to introduce themselves,
and I think
we will start on my right, Dr. Doroshow,
if you
would introduce yourself, please.
DR. DOROSHOW: Jim Doroshow, NCI.
DR. BRAWLEY: Otis Brawley, Medical
Oncology and Epidemiology, Emory
University.
DR. D'AGOSTINO: Ralph D'Agostino,
Biostatistician, Boston University.
DR. PROSCHAN: Mike Proschan,
Statistician, National Heart, Lung, and
Blood
Institute.
DR. GRILLO-LOPEZ: Antonio Grillo-Lopez,
Industry Representative.
DR. MORTIMER: Joanne Mortimer, Medical
Oncology, University of California at San
Diego.
DR. PERRY: Michael Perry, Medical
142
Oncology, University of Missouri, Ellis
Fischel
Cancer Center.
DR. HUSSAIN: Maha Hussain, Medical
Oncology, University of Michigan.
DR. MARTINO: Silvana Martino, Medical
Oncology, Cancer Institute Medical Group,
Santa
Monica.
DR. REAMAN: Gregory Reaman, Pediatric
Oncology, George Washington University.
DR. RODRIGUEZ: Maria Rodriguez, Medical
Oncology, M.D. Anderson Cancer Center.
DR. LEVINE: Alexandra Levine,
Hematology/Oncology, University of
Southern
California.
MS. HAYLOCK: Pam Haylock, Oncology Nurse,
University of Texas Medical Branch in
Galveston,
and I am the Consumer Representative.
DR. IBRAHIM: Amna Ibrahim, Medical
Officer, FDA.
DR. SCHER: Nancy Scher, Medical Officer,
FDA.
DR. COLMAN: Eric Colman, Medical Officer,
FDA.
DR. AVIGAN: Mark Avigan, Office of Drug
Safety.
143
DR. TEMPLE: Bob Temple, Office Director,
OD-I.
DR. PAZDUR:
Richard Pazdur, FDA.
DR. MARTINO: Thank you.
Next, the Conflict of Interest
Statement
by Ms. Clifford.
Conflict of Interest
Statement
MS. CLIFFORD: Thank you. The following
announcement addresses the issue of
conflict of
interest and is made a part of the record
to
preclude even the appearance of such at
this
meeting.
Based on the submitted agenda
and all
financial interests reported by the
committee
participants, it has been determined that
all
interests in firms regulated by the
Center for Drug
144
Evaluation and Research present no
potential for
appearance of a conflict of interest with
the
following exceptions:
In accordance with 18 U.S.C.
208(b)(3),
full waivers have been granted for the
following
participants. Please note that the
following
interests waived are unrelated to Zometa,
Aredia,
and its competing products.
Dr. Otis Brawley has been
granted waivers
under 208(b)(3) and 21 U.S.C. 505(n) for
owning
stock in a competitor, valued between
25,000 and
50,000 per firm.
Dr. Michael Perry has been
granted a
waiver under 21 U.S.C. 505(n) for owning
stock in
two competitors, valued between 5,001 to
$25,000.
Because his stock interests fall below
the de
minimis exception allowed under 5 CFR
2640.202(b)(2), a waiver under 18 U.S.C.
208 is not
required.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
Agency's Freedom of Information Office,
Room 12A-30
145
of the Parklawn Building.
With respect to the FDA's
invited industry
representative, we would like to disclose
that Dr.
Antonio Grillo-Lopez is participating in
this
meeting as an acting industry
representative acting
on behalf of regulated industry. Dr. Grillo-Lopez
is employed by Neoplastic and Autoimmune
Disease
Research.
In the event that the discussions
involve
any other products or firms not already
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement,
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any
firm whose products they may wish to comment
upon.
Thank you.
DR. MARTINO: Thank you.
Dr. Pazdur will now address the
group and
146
give us some guidance as to the nature of
this
problem and what our agenda is.
Opening Remarks
DR. PAZDUR: Pamidronate and Zometa are
potent intravenous bisphosphonates. Aredia
received approval for hypercalcemia
malignancy in
1991, for multiple myeloma in 1995, and
for
osteolytic bone metastases from breast
cancer in
1996.
Zometa was approved for hypercalcemia
malignancy in August of 2001 and for a
broad bone
metastasis indication in February of
2002.
In 2002, the FDA received 9
spontaneous
reports for osteonecrosis of the jaw in
patients
with malignancy whose treatment regimens
included
intravenous bisphosphonates.
In 2003, the first published
reports of
ONJ in patients treated with intravenous
bisphosphonates appeared in the
literature.
In a high proportion of cases,
there was
an association with a recent dental
procedure.
These patients had no history of
radiation therapy
to the head and neck.
The Zometa package insert was
updated in
September 2003 to include information
about
osteonecrosis of the jaw in the Adverse
Events
147
section.
The Aredia package insert was also
updated in November of 2003.
In August 2004, changes were
made to the
Precautions section of the Zometa label,
followed
by a parallel change to the Aredia label,
regarding
osteonecrosis of the jaw. Novartis issued a Dear
Doctor letter in September 2004 regarding
osteonecrosis of the jaw.
The purpose of bringing to ODAC
the
problem of osteonecrosis of the jaw in
association
with intravenous bisphosphonates is to
highlight a
drug safety issue in oncology and
stimulate
consideration of how post-marketing
safety issues
in oncology should be addressed.
Although there have been
anecdotal reports
of ONJ in association with oral
bisphosphonates
administered for osteoporosis, we wish to
limit
today's discussion to osteonecrosis of
the jaw in
association with Zometa and
pamidronate. Less data
148
is available for the oral
bisphosphonates, and the
risk-benefit considerations are different
for
patients with malignancy compared to
patients being
treated for benign bone diseases.
Thank you.
DR. MARTINO: Thank you, Dr. Pazdur.
Dr. Nancy Scher will now
describe the
history of Zometa and Aredia and its
regulatory
process.
FDA Presentation
Regulatory History of Zometa
and Aredia
DR. SCHER: Good morning.
I shall provide
an overview of the regulatory history of
the
approval of Zometa and Aredia, and also
provide
some chronology regarding the recognition
of an
unusual adverse event occurring in some
patients
treated with intravenous bisphosphonates.
Aredia is approved for
treatment of
patients with osteolytic bone metastases
of breast
cancer and osteolytic lesions of multiple
myeloma
in conjunction with standard
antineoplastic
therapy.
It is also approved for
hypercalcemia of
malignancy and Paget's Disease of bone.
You have heard the Aredia
approval dates.
149
Again, in 1995, there was an approval for
osteolytic lesions of multiple myeloma,
and in
1996, for breast cancer.
The approval of Aredia
represents a
regulatory precedent. Skeletal related events, or
SRE, were defined and used as a basis for
the
approvals in the bone metastases
indications for
Aredia and subsequently for Zometa.
This slide shows you the four
components
that define that composite endpoint -
pathologic
fractures, radiation therapy to bone,
surgery to
bone, and spinal cord compression.
The multiple myeloma indication
for Aredia
was based on a single double-blind,
randomized,
placebo-controlled trial, where Aredia 90
mg
monthly intravenously was given for 9
months.
Aredia demonstrated superiority to placebo
for several SRE endpoints.
For breast cancer, there were
two
150
licensing trials for Aredia. They were
double-blind, randomized,
placebo-controlled,
Aredia 90 mg IV every 3 to 4 weeks was
given for 24
months.
Patients were required to have
at least 1
osteolytic lesion. In one study, patients were
receiving chemotherapy, and in the other
study,
patients were receiving hormonal therapy.
Together, the trial results
supported the
indication for Aredia in patients with
metastatic
breast cancer.
Zometa is approved for
treatment of
patients with multiple myeloma and
patients with
documented bone metastases from solid
tumors, in
conjunction with standard antineoplastic
therapy.
Prostate cancer should have progressed
after
treatment with at least one hormonal
therapy.
Zometa is also approved for hypercalcemia
of
malignancy.
Zometa was approved for
hypercalcemia of
malignancy in August of 2001. At that time,
Novartis submitted a supplemental NDA for
the bone
151
metastases indications to FDA. FDA reviewed this
application as a priority NDA.
In February 2002, Zometa was
approved for
the bone metastases indications. This approval for
Zometa expanded the indications for
bisphosphonates.
Zometa was approved for a broad
range of
solid tumors, not limited to breast
cancer as
Aredia had been. Furthermore the lesion type was
not limited to osteolytic lesions. However, the
optimal duration of therapy could not be
defined
from the trial design.
The oncology indication for
Zometa was
based on 3 randomized trials. The multiple
myeloma/metastatic breast cancer trial
randomized
patients to an active control of Aredia
90 mg, for
Zometa 4 mg.
The remaining 2 trials were
placebo-controlled, 1 in prostate cancer
and 1 in
other solid tumors.
The primary endpoints were time
to first
SRE and proportion of patients with SRE.
This slide provides some
additional detail
about the Zometa registration
trials. You can see
the multiple myeloma/breast cancer trial
was
152
relative large, greater than
1,600-patient trial,
and it had a non-inferiority design.
Time to first SRE was the
preferred FDA
endpoint. You see information about that
presented.
For prostate cancer and other solid
tumors, Zometa
4 mg demonstrated superiority to
placebo. For
multiple myeloma or breast cancer, Zometa
4 mg was
non-inferior to Aredia 90 mg.
This slide shows the number of
cases of
osteonecrosis of the jaw reported to the
FDA by
year.
In 2001, there were no such reports.
In
2002, there were 9 cases reported of
patients with
osteonecrosis of the jaw who were receiving
intravenous bisphosphonates as part of
their
treatment regimen.
There were additional cases in
2003, and
more cases in the first half of May of
2004. These
numbers were provided to me by the Office
of Drug
Safety.
As of this time, as you will hear in
153
subsequent presentations, the number of
reports is
in excess of 600.
This slide lists a fairly
comprehensive
review of the literature of reports of
osteonecrosis of the jaw associated with
bisphosphonates. You will see the chronology is
somewhat similar to the chronology of the
adverse
events reported to the FDA.
I want to point out that this
literature
pretty much starts in 2003. Most of the reports
are abstracts or very brief reports, and
particularly earlier on, we are limited
to the oral
surgery literature.
The most detailed report that I
am aware
of was Dr. Ruggiero's paper in May of
2004,
reporting 63 cases of osteonecrosis of
the jaw in
patients taking bisphosphonates. Again,
this was in
the
oral surgery literature.
Subsequent speakers will
provide you with
details of the clinical manifestations of
this
adverse event. This is just a very brief and
limited description of some of the
features
154
characterizing these patients.
The patients with ONJ had
diagnoses of
malignancy. They had not received head
and neck
radiotherapy. Their treatment regimens included
intravenous bisphosphonates. A high proportion of
these patients had recent invasive dental
procedures.
In response to reports of ONJ
in cancer
patients treated with IV bisphosphonates,
changes
were made to the labels of Zometa and
Aredia.
The Adverse Events section was
updated to
include ONJ in September of 2003 for
Zometa, and
then Aredia in October. The Precautions section
for both drugs were updated in August
2004.
The next two slides paraphrase
the
contents of the current Zometa
label. For
reference, the actual language from these
sections
of the labels is included in the document
which
contains discussion points distributed
this
morning, and it was also in the
Committee's
background documents if you would like to
refer to
the label information.
I think I need to go back.
The Adverse Events section reported
that
ONJ had been seen in patients treated
with
155
bisphosphonates. The majority of cases were
associated with a recent invasive dental
procedure.
It stated there were multiple risk
factors for ONJ,
including cancer, chemotherapy,
radiotherapy,
corticosteroids, et cetera.
It stated that although
causality cannot
be determined, it would be prudent to
avoid dental
surgery as recovery may be prolonged.
The Precautions section
reiterates some of
the previous information, is placed in a
more
prominent section of the label, and
provides some
new information, as well.
Osteonecrosis of the jaw is seen in cancer
patients, many of whom were also
receiving
chemotherapy and corticosteroids, the
majority of
cases associated with dental
procedures. Many
patients had signs of local infection
including
osteomyelitis.
Baseline dental exam should be
considered
156
if there are risk factors such as cancer,
chemotherapy, corticosteroids, poor oral
hygiene.
While on treatment, avoid
invasive dental
procedures. If a dental procedure is required,
there is no data to say if discontinuing
therapy
reduces the risk of ONJ.
In summary, Zometa and Aredia
are
effective drugs for the bone metastasis
indication.
An unusual adverse event has
been
identified in some patients treated with
intravenous bisphosphonates.
The true incidence of
osteonecrosis of the
jaw is unknown.
Thank you very much for your
attention,
and you will hear a lot more about this
from
subsequent speakers.
DR. MARTINO: Thank you, Dr. Scher.
Our next speaker is Ms. Carol
Pamer from
the Office of Drug Safety. She will speak on
Post-Marketing Safety Assessment of
Osteonecrosis
of the Jaw with Pamidronate and
Zoledronic Acid.
Post-Marketing Safety Assessment of
Osteonecrosis
of the Jaw: Pamidronate and Zoledronic Acid
MS. PAMER: Good morning.
My name is
Carol Pamer and I am a safety evaluator
in the
157
Office of Drug Safety.
I will be presenting a brief
overview of
the FDA's spontaneous reporting system
named AERS,
including its strengths and
limitations. I also
will provide a high-level summary of case
reports
of ONJ that have been reported with
pamidronate and
Zometa.
I am going to discuss specific
difficulties in assessing the case
reports, and
finally, our epidemiologist, Carolyn
McCloskey, has
prepared some comments concerning the
epidemiological issues concerning the study
of this
event, and I will present those remarks
on her
behalf.
Generally speaking, a
spontaneous
reporting system is a mechanism for
clinicians and
patients to report adverse events that
occur after
a drug has been marketed in a larger and
more
diverse group of patients after the
clinical trials
158
are over.
In the U.S., these case reports
are known
as Med Watch reports, and the database
which houses
them is the AERS database. FDA has maintained a
reporting system since 1969. Over time,
modifications have been made to the
system and the
database primarily as computer
capabilities have
increased.
There are a number of factors
which affect
reporting patterns and quality of case
reports that
FDA receives. Some types of adverse events are
more or less likely to be reported than
others, and
some examples of that are cases with a
fatal
outcome or severe outcome, special
populations,
such as children, or adverse events that
are
usually suspected to be related to drug
use.
The type of product and
condition for use
can affect reporting. Prescription drug products
require patient interaction with the
health care
system, so those events related to the
products may
be detected more frequently.
Reporting for a drug tends to
be heaviest
159
in the first few years after marketing,
and then it
tapers off over time. Media attention or medical
publishing will affect that. Finally, the quality
and extent of reporting varies by
pharmaceutical
company, and regulations affect that
directly, as
well.
AERS is an uncontrolled means
for
gathering information about a marketed
drug, so
some case reports are better documented
and more
convincing of a possible relationship
than others.
Critical elements of a case
report, which
are evaluated, include the time to onset
or
temporal relationship of the adverse
event to the
drug, assessment of whether the patient
has any
symptoms of the adverse event prior to
starting a
product, and a baseline health status can
help in
documenting that.
Evaluating drug dechallenge is
drug safety
jargon for evaluating whether the
symptoms of the
adverse event went away after the drug is
stopped.
Drug rechallenge refers to
testing whether
the adverse event recurs if the drug is
restarted.
160
If both dechallenge and rechallenge are
positive,
that can be a pretty strong indicator
that an
adverse event is related to a drug.
Another critical issue in
evaluating the
strength of a case report is determining
whether
there are other explanations for the
events.
Typically, these are other medical
conditions or
other drugs.
The other items, consistency with
pharmacologic effects, known effects in
the class,
and controlled trials attempt to make an
argument
that the drug caused the events rather
than they
were simply associated with it.
There are some limitations of
using
spontaneous reports for investigating
drug safety.
The system is passive or voluntary in the
U.S., so
in many cases, are not reported. This will also
vary from drug to drug and over time.
Reporting bias exists in that
some events
are more likely to be reported than
others. The
quality of cases is highly variable. You have many
reporters and reports are often
incomplete.
161
Duplicated cases can be submitted and
this requires
a case review to sort those out.
Very importantly, we don't know
what
proportion of the true number of cases of
an
adverse event in the population are
reported to
AERS, which is the numerator of an
incidence rate,
and we don't know the true counts of how
many
people take the drug. That is usually estimated by
drug usage data at this point and that is
the
denominator of an incidence rate.
So, with these limitations in
mind, there
are adverse events for which AERS is best
applied.
Its best functionality is for detecting
safety
signals, the early warnings that there
might be a
problem with the drug.
The best documented convincing
cases can
be used to develop a descriptive case
series. The
more well established a diagnosis is for
an adverse
event, the more likely it will be noted
by a
clinician and also be readily identified
in AERS.
Events with a low background
rate in the
general population or that are rare can
be more
162
readily detected with AERS, and events
with a
shorter latency period lend themselves to
detect
signal detection more readily.
Now, I will just present a
quick summary
of the reports of osteonecrosis and
osteomyelitis
that have been reported for the two IV
bisphosphonates.
An in-depth review of 139 cases
was
previously conducted by Jenny Chang of
the Office
of Drug Safety, and a copy of that review
was
included in the background package for
this
meeting, and my tables just provide a
brief status
update to that review, which my numbers
are
cumulative though.
Novartis Pharmaceuticals will
be
presenting a more detailed overview of
the cases.
This slide lists the details of
the search
used for this update, and there are two
important
differences to point out. The case series by Jenny
Chang included cases of osteonecrosis at
other
sites, although most cases involved the
jaw, and
the Novartis data differ due to slight
differences
163
in search terms, different cutoff date,
and they
don't have reports from other
manufacturers.
It is probably not very visible
all the
way back there, so I will go through it.
This slide summarizes which of
the two
drugs was indicated as being prescribed
in the
reports.
There are a total of 654 in which the two
drugs are mentioned. The first listing is
pamidronate only, which was 136 or 21
percent of
the reports.
Pamidronate or Zometa, its
sequential use
was defined in this way as any history of
use
primarily to keep the solo use cleaner
and the
drugs persist in bone, so it was just
neater to
keep solo therapies separate, and then if
there was
any mention of a history of the two,
then, this is
in this category, and that constituted 28
percent
of these reports.
Then, zoledronic acid were 49
percent, and
then one of the two drugs, oral history
again of
another bisphosphonate, that was about 2
percent of
the 654.
The numbers just grossly seem to be in
164
proportion to the use of the products.
This table summarizes the
primary
indication for use listed in the
report. Most
patients were being treated for
cancer. Multiple
myeloma was approximately 34 percent
either with or
without another. Most of them were alone. Some
mentioned a history of other cancer, so
those were
just tallied separately. Breast cancer,
approximately 27 percent if you consider
other
cancers mentioned. Prostate cancer, around 7
percent.
There were 16 percent cancer
unspecified
or
other type. Most of those were
unspecified.
Osteoporosis, osteopenia, and osteolysis,
which is
probably a cancer, that was 1 percent,
and then 15
percent of the cases didn't have an
indication
listed at this point.
At this point, I will discuss specific
difficulties encountered in evaluating
these cases
reported with the two drugs.
One of these is the increased
rate of
reporting due to publicity makes the
assessment of
165
the usual pattern of reporting difficult.
Confounding factors were present in many
of the
cases.
Assessment of drug dechallenge
is
confounded. I will explain that later.
Establishing a pattern in the time to
onset after
the drug was started is also difficult.
Confounding factors were
present in many
of the case reports primarily due to the
nature of
the underlying disease being treated.
This list includes the various
drugs,
procedures, and medical conditions which
theoretically could have some effect on
bone and
increase the risk of ONJ.
Spontaneous reports, as
frequently
happens, had missing information, which
was also
true in this case series.
A clear assessment of the drug
dechallenge
was limited by the fact that these drugs
persist in
bone, and the duration of action is
prolonged, so
even though the drug is stopped, the
actions
persist, and a prolonged period would be
required
166
to determine whether the patient completely
recovered.
Many patients required
therapeutic
interventions, so this confounds
evaluating whether
the only factor in the patient recovering
was, in
fact, stopping the drug.
Time to onset was also
difficult to
evaluate in that the detection of ONJ was
often at
a later stage, for example, when a dental
extraction was conducted, but failed to
heal.
We didn't search for cases
where possible
early symptoms were present, such as jaw
pain or
tooth loss, but no definitive diagnosis
had been
made.
That was beyond the scope of the search.
Information on the early symptoms was
missing in a
number of cases.
Now, I will present Carolyn's
remarks on
the epidemiological perspective of
studying this
condition.
Studying osteonecrosis of the
jaw is the
challenge and even more so with these
drugs. It is
a rare event and obtaining a population
background
167
rate for comparison is difficult, and it
is
especially difficult for multiple myeloma
and
breast cancer patients.
The difficulty in identifying
ONJ cases in
existing databases is that ONJ does not
have a
specific code for searching a
database. For
example, there is no specific ICD-9 code
for ONJ.
It is also difficult to
determine an
accurate number of patients exposed to IV
bisphosphonates due to the fact that many
are given
in free-standing clinics.
Finally, it will be difficult
to identify
an equivalent cancer control or
comparison group
for study of ONJ associated with the IV
bisphosphonates.
Some potential sources of data
include
oncology clinics, which could provide a
cohort of
patients exposed to IV
bisphosphonates. A
potential source for determining a more
accurate
count of cases could be dentists and oral
surgeons.
Dentists could provide cases of dental or
jaw
infections, jaw pain, or osteomyelitis of
the jaw
168
regardless of drug exposure.
A national registry could
provide a means
to collect all cases of ONJ identified in
different
settings.
To summarize the epi
perspective, there
are limitations in identifying and
capturing cases
and quantifying IV bisphosphonate
exposure in
electronic, pharmacoepidemiological and
post-marketing surveillance data
including HMOs and
passive reporting databases.
Chart review studies at major medical or
cancer centers have their own limitations
in
capturing all ONJ cases with these
products.
Obviously, a randomized,
controlled
clinical trial would be superior to
studying this
in currently available databases,
however, there
are limitations to controlled clinical
trials
especially since this condition is rare.
A national registry of ONJ
cases should be
considered.
To conclude, in spite of the
limitations
of the available drug safety tools, we
believe that
169
these cases present a highly plausible
safety
signal.
Some of the reasons for this are most of
the cases that have been reported affect
the jaw,
lending plausibility to a specific or
common
mechanism.
A large number of reports of a
generally
rare event have been received. The duration of use
of the drug relative to diagnosis of a
chronic
condition is fairly short, and serious
adverse
event reports tend to be captured well in
AERS.
We would suggest that other
studies be
conducted to attempt to identify which
patients may
be most susceptible or if modification to
treatment
regimens would reduce the risk.
Thank you.
DR. MARTINO: Ms. Pamer, on behalf of the
committee, I need to ask you to clarify
some things
for me.
Can you give me a better
understanding of
who tends to report or who has the
ability to
report toxicities to the FDA system? I am assuming
it's patients, I am assuming it's physicians. Are
170
pharmaceutical data also incorporated
into that?
MS. PAMER: Many of the reports we
received are reports that have come to
the company,
and then the company is required to send
those to
FDA, and patients, there are means
through the
Internet.
You can also report directly to FDA
through Med Watch. So, this is the Med Watch data
collection system.
DR. MARTINO:
So, anyone is able to access
the system. In general, where does most of the
information come from, is it physicians,
is it
pharmaceuticals, or is it individual
patients? In
general, I am asking you, not specific to
this
toxicity.
MS. PAMER: Most of reports are, and in
this case series, most of them were
dentists,
M.D.'s, or oral surgeons. They might have reported
first to the company, but they come to
us, but they
are
mostly health care providers.
DR. MARTINO: So, a patient would be the
least likely person to report directly to
you, do I
understand that correctly?
MS. PAMER: Less frequently they do, but
it depends. There are some issues where they
report a lot through the Internet.
171
DR. MARTINO: So, once someone initiates a
report, I am assuming that there is
information
that is requested from them, that gives
you certain
details.
Is there any human interaction to then
get additional data, or what is the
extent of what
is obtained from such a report?
MS. PAMER: Probably the company could
give you an idea of how they collect the
information on how their system works.
DR. MARTINO: My question--I may ask the
same question of them--but my question of
you is,
the FDA system is really the one I am
interested
in, once I, as a human being, report that
I have
had a toxicity, I am assuming there is
some
questions I will be asked to answer, who
are you--
DR. AVIGAN: Can I just participate?
DR. MARTINO: Can someone help me?
DR. AVIGAN: Yes.
DR. MARTINO: Thank you.
DR. AVIGAN: We actually have a number of
avenues by which we can address those
issues, when
a signal is seen and there are questions
that are
raised that require follow-up, we have
the
opportunity to ask the manufacturer, the
company,
to go and do sort of specified follow-ups
through
172
discussions that we would have with them.
Another approach is that on
particular
issues, we can contact the reporter, the
reporters
are listed in our Med Watch form, and get
direct
follow-ups from them. So, I would say that there
are a number of possibilities, and these
are
generally conceived of based on the case
at hand.
The retrospective look at
safety problems
typically is limited, because you don't
get
information in real time, and there is a
general
problem of getting a full plate of
information on
particular cases when you are going
retrospectively
to cases that have been reported about
previous
events.
DR. MARTINO: That does answer my
question.
Help me to understand what would
173
stimulate the system to recognize that
there is a
potential problem. I am assuming that all kinds of
things get reported to you and somehow
someone has
to sift through what is noise and what do
you sort
of focus in on. Answer that for me, please.
DR. AVIGAN: Right.
It really is on a
case-by-case basis, and I think Carol has
outlined
some of the points that would raise our
concerns
about a signal being truly linked to a
risk and a
causally related event.
Some of the points are that the
event that
is being reported has a low background
rate or
would not be necessarily expected to
occur in the
kind of cluster that it is being reported
at. So
the background effect, the temporal
association,
and then the quality of the cases
themselves.
In addition to the counting of
the total
aggregate of cases, we actually with
specificity
look at individual cases, and some cases
based upon
the information that is provided allow us
to create
a
kind of probability analysis of causality, so
that it is a different dimension of
looking at the
174
question of is the drug going to the
specific
adverse event.
In this case, one of the
features of this
particular adverse event is that the
anatomical
site specificities are quite striking,
that is, the
osteonecrosis search is not anatomically
specific,
but when we pull the cases and look at
what these
reports are, they are very, very
strongly, well,
biased.
Most of the cases actually are
of the jaw,
which would be different than, let's say,
an
osteonecrosis search for the general
background
population or for other medications. As an
example, that would point towards a
signal, for
example.
DR. MARTINO: Thank you.
Next, Dr. Brian Durie from
Cedars-Sinai
will discuss Osteonecrosis of the Jaw in
Myeloma:
Time Dependent Correlation with Zometa
and Zometa
Use.
Osteonecrosis of the Jaw in
Myeloma: Time
Dependent Correlation with Zometa
and Zometa Use
DR. DURIE: Members of the Committee,
ladies and gentlemen, I appreciate the
opportunity
to present these data to you today. These data
175
were presented at the American Society of
Hematology in oral session in December
and will be
published shortly.
The basis for these studies
feeds in
exactly with the discussion that was just
being
held.
This is a study that was conducted as a
collaboration between the International
Myeloma
Foundation, which is a nonprofit entity
based in
California, and Cancer and Research and
Biostatistics, which is the research
entity run by
John Crowley. Many of you will know that that is
the stat center for the Southwest
Oncology Group.
So, this is a collaboration
between the
IMF and a rather well-known statistical
group.
The International Myeloma
Foundation
provides a number of functions. One of them
relates to patients, and that is an
educational
function, and that is serviced by an 800
hot line,
and it is serviced by a variety of
seminars that
176
are held across the country, as well as
help to
support groups.
So, in terms of receiving a
signal, if
something unusual is happening, and
patients want
to find out, they are quite likely to
call our 800
number.
So, we are one of the first people who
might hear about a new problem that is
emerging.
In this particular study, I
would like to
emphasize one other point, and that is
that the
purpose here was to try to identify
individuals
with osteonecrosis of the jaw, and so we
could
evaluate and understand these cases.
We were not in a position to
evaluate the
denominator for these studies, so this is
not a
study related to the incidence. It is a study
related to an analysis of patients who
actually
have this problem.
So, just to show you visually,
well, what
is osteonecrosis of the jaw, and these
pictures on
the left were provided by Sal Ruggiero,
who is
present here today on my right, and was
the first
person to report a case series of 63
patients in
177
the Journal of Oral and Maxillofacial
Surgery.
So, it covers a spectrum. The first part
of the spectrum is exposed bones, bone
spicules.
The end of the spectrum is where there
has been
significant underlying osteonecrosis of
the jaw,
which can indeed be a substantial problem
which
involves poor healing, secondary
infection, and
loss of teeth, and in some cases,
significant parts
of the jaw.
There are several mechanisms
that have
been proposed linked in with this related
to the
disruption of the bone remodeling cycle.
So, how frequent is
osteonecrosis? As you
have heard, we do not really know the
true
incidence of this except that it was rare
in the
past, and it is very clear that it was
rare in the
past and now we are seeing it.
Our 800 number is ringing. Patients are
coming in to see dentists and oral
surgeons. This
was not happening before for myeloma
patients. Dr.
Marx reported his first 36 cases in
2003. Dr.
Ruggiero, who is right here, reported his
patients
178
in 2004.
Those were 63 patients that were
diagnosed between 2001, February, and
2003.
Of note, there are two aspects
about his
patients. They did include some patients
that had
been treated with oral bisphosphonates,
the
majority with IV bisphosphonates. They
did include
a
few patients who did not have cancer, patient who
had osteoporosis only.
Here, more recently, in myeloma
groups
around the country, clearly, we are
seeing many
more of those patients. At the patient seminars
that I mentioned earlier, these are seminars
where
1- or 200 patients would be present at a
time.
Consistently now, there are 5,
10,
sometimes more patients in the audience
who have
osteonecrosis, and this translates in
that setting
to maybe 2 to 5 percent of the people who
are in
that setting. How that translates to the wider
population, I don't know.
For me, this was a very
important
opportunity because it allowed me to structure
the
questionnaire that I am going to show you
today. I
179
had met a lot of patients who had
osteonecrosis of
the jaw.
I understood how it had come to
attention, how it manifested.
I knew, for example, that most
of them
knew that they did, in fact, have
osteonecrosis of
the jaw.
They had seen a dentist, they had seen an
oral surgeon. They knew what that was, so they
could answer that question yes or no.
So, was this a diagnosis missed
prior to
2001?
I think not. Certainly from the
bottom
picture that I showed you, this is not
something
that would go unnoticed.
What has caused the increased
frequency?
Well, both Dr. Marx and Dr. Ruggiero
certainly drew
attention to the bisphosphonates.
So, what are the questions
right now?
From our perspective in this
questionnaire, we
looked at is the likelihood of
osteonecrosis ONJ
linked to the use of the Aredia and
Zometa in the
patients that responded to our survey, to
what
extent were other therapies impacting the
frequency
and the likelihood, were there
identifiable risk
180
factors, what was the magnitude or
severity of the
problem, and what we thought was quite
important
was is this a problem confined to myeloma,
is it
more common in myeloma versus, for
example, breast
cancer.
So, we surveyed both myeloma
patients and
breast cancer patients, which is
important in one
particular aspect, and that is that the
treatment,
the other treatments for breast cancer
and myeloma
are obviously quite different. For
example breast
cancer patients are not frequently
treated with
thalidomide and high-dose dexamethasone.
So, this was an anonymous
web-based survey
that was conducted in August of
2004. It included
1,203 patients, of which 904 had myeloma,
299 had
breast cancer. They were recruited by a variety of
electronic means - through the IMF web
site,
through ACOR, but also through a number of
established listservs, Nexcura and Y-Me,
National
Breast Cancer Organization.
A number of very, very specific
questions
were asked with pop-downs where it was
possible to
181
select a variety of answers.
The setting for this, in
structuring the
questions, was the treatments that are
available
for myeloma. The therapies have mostly been
available for several decades, and you
can see
here, starting at the bottom, Melphalen
and
prednisone, radiation therapy including
sometimes
to the head and neck available for a long
time.
Steroids have been used for several
decades, stem
cell for two, three decades now.
At the top here, you see really
three
types of agents that have been available
more
recently:
the bisphosphonates, thalidomide, and
Valcade.
Valcade has been available sufficiently
recently that it is not really an
issue. So, we
focused on thalidomide, bisphosphonates,
and
steroids primarily as potential risk
factors, but
we looked at all of these therapies.
Of 1,203 patients, 904 myeloma, there
were
62 myeloma patients who had osteonecrosis
of the
jaw.
There were 54 who, in addition, these are 54
additional patients who had suspicious
findings.
182
These were patients who had not been
given a
diagnosis of osteonecrosis of the jaw,
but had
suspicious findings that we identified as
bone
erosions, bone spurs, or exposed
bone. These were
specific questions that were asked.
For breast cancer, 13 with a
diagnosis of
osteonecrosis, 23 with 1 or more of the
suspicious
findings.
The first thing that we noticed
was that
it was more likely for osteonecrosis to
occur over
time.
In this case, it was from the time of
diagnosis. You will see I used different time
markers here. This one is time from diagnosis. We
also looked at the time from the start of
bisphosphonate therapy, for example.
You will see this curve has got
two parts
to it, a very shallow curve here, and
then a
sharper part to the curve here. So, this is what
we decided to investigate in more detail.
The first thing that we looked at
was the
time frequency over the last few years,
57 patients
where we had data. These are the number of cases
183
in 2004, 321. There were cases in the past. There
were patients related to head and neck
irradiation.
The same pattern for breast cancer. You
can see a
striking increase in the last 2 1/2, 3
years.
This shows you the frequency of
use of
other therapies in addition to the
bisphosphonates.
You can see here the 62 patients,
myeloma,
osteonecrosis of the jaw, 57 had been
taking
bisphosphonates, 3 had head and neck
irradiation,
so there are actually 2 patients who had
not had
head and neck irradiation or were taking
bisphosphonates.
You can see there was a pattern
of Aredia
and Zometa use as listed here. We are going to go
into that in more detail. A majority of patients
had obviously used steroids, some
prednisone, some
dexamethasone, and about half the
patients had
taken thalidomide at some point.
This shows you the increasing
incidence of
osteonecrosis among the respondents from
the date
of diagnosis, looking at the use of
Zometa, Aredia
alone, patients who had been taking
Aredia, but
184
switched over to Zometa when it became
available,
and those who had not taken any
bisphosphonate.
You can see the little blue one
over here.
We are going to look at that in more
detail. That
is Zometa, which represented 22 percent
of the
patients, 28 percent to Aredia alone, 45
percent
had actually switched over from Aredia to
Zometa.
So, interestingly, this occurred more
frequently in
this series and patients who had switched
from
Aredia to Zometa.
We were quite interested in the time to
the onset in the two major groups there,
and this
was quite striking. Patients who had been
taking
Zometa, the average time, the mean time
18 months
to the onset of osteonecrosis, 19 months
to the
onset of suspicious findings. Aredia, 6 years, 72
months, somewhat shorter, to the onset of
suspicious findings.
Now, obviously, we realized
that these
drugs have not been on the market the
same length
of time, so we have done some corrections
related
to that, that you will see in a
moment. This is
185
obviously statistically different.
This just shows you visually,
the blue is
Zometa, the red is Aredia, for myeloma
and for
breast cancer. The patients were more frequently
either taking Zometa or switched over to
Zometa at
the time that they developed the
osteonecrosis or
the suspicious findings.
In this case, we looked at the
exact
length of the treatment with Aredia or
Zometa with
respect to the likelihood of getting
osteonecrosis
of the jaw. Again, you can see there is a
difference related to Zometa or those who
switched
from Aredia to Zometa versus Aredia
alone.
In all three cases, obviously,
it is going
up over time, of course.
Now, to compensate for the fact
that the
Zometa has only been on the market for
three years
at the time of our study, we censored the
data at
three years and compared Aredia with
Zometa with
three-year censoring and looked at the
log rank p
value estimates at 36 months.
Zometa is in blue, and you can
see here
186
that it occurred more frequently. I think that
what caught our attention, and our
concern
actually, was this is 12 months right
here. You
can see that there were clearly patients
having
osteonecrosis of the jaw within the first
year of
therapy, the mean value was 18 months but
certainly
cases occurring within the first 6 to 12
months.
We looked at other
factors. This compares
patients who had been taking prednisone
and not
taking prednisone. You can see that these are the
events here. No difference in the likelihood with
and without prednisone, although in a
variety of
other studies, there was some increased
risk in
patients concomitantly taking steroids,
but this
did not play out over time.
We also looked at thalidomide
and
dexamethasone, and again there were some
suggestions that patients taking
thalidomide and
dexamethasone were at higher risk,
however, this
did not play out in the time dependent
regression
analyses, so that both for thalidomide
and
dexamethasone, there was no difference using
the
187
log rank method.
So, what suddenly occurred to
me was,
well, why did we start to see this
problem in 2001,
and I suddenly realized when I was
looking at the
statistics that 6 years is the average
time to the
onset with Aredia, well, 6 years is the
time since
Aredia came on the market, 18 months is
the time
for Zometa. Well, that is the time since Zometa
has been on the market.
So, there is a coincidence of
time frames
here related to the time since these
agents have
been in the marketplace.
There is one other very important
point,
and that is that 6 years of Aredia, how
many
patients with myeloma are alive and could
be taking
Aredia for 6 years. Well, obviously, that is less
than 20 percent of the patients. So, the number of
patients at risk taking Aredia at 6 years
is much,
much lower.
Just to compare the data with
myeloma and
breast cancer, since the therapies are so
much
different, there was no difference in the
188
likelihood with censoring at 3 years
between the
breast cancer patients who responded and
the
myeloma patients who responded.
However, if you looked at
Zometa and
Aredia, the difference persisted. It was much more
likely that Zometa could be associated
with
osteonecrosis or suspicious findings
early in both
myeloma and breast cancer.
What were predisposing
factors? It was
quite striking and has been emphasized by
several
speakers that the predisposing factor is
prior
dental problems including surgery and all
kinds of
dental issues, and here a very striking
difference.
Patients likely to get this problem are
highly more
likely, with myeloma and breast cancer,
to have had
underlying dental problems.
So, among the respondents,
duration of
therapy is clearly an increased risk
factor. With
the 36-month estimates, Zometa is more
likely than
Aredia to be associated with
osteonecrosis.
None of the other therapies in
the time
dependent analyses impacted this
likelihood.
189
Patients with prior dental problems were
much more
likely to develop osteonecrosis of the
jaw.
Our preliminary working
conclusions, and
people are going to be able to discuss
elements
that might derive from this, but clearly,
precautions related to dental care could
impact the
likelihood of this disease, and
obviously,
precautions related to bisphosphonates
could impact
the likelihood of this problem.
I would like to thank the
groups and
individuals who participated in this
project,
particularly the organizations who
contributed
patients, the statistical center, and
particularly
Vanessa Bolejack, who did the statistical
analysis.
Thank you.
DR. MARTINO: Thank you, Dr. Durie.
I would now like to turn to
Novartis and
ask Dr. Young to present their data.
Sponsor Presentation - Novartis
Pharmaceuticals
ONJ Reported in Bisphosphonates
Treated
Patients - An Overview
DR. YOUNG: Good morning.
I am Dr. Diane
190
Young, Vice President of Clinical
Development-Oncology at Novartis. I am an
oncologist by training.
I would like to start by
thanking the
Chair, ODAC panel members, as well as the
FDA today
for the opportunity to share our current
understanding of an important clinical
entity,
osteonecrosis of the jaw. There has been an recent
increase in awareness and interest in
this
condition due in part to the efforts of
Drs.
Ruggiero, Marx, and Durie, as well as the
FDA and
Novartis.
In this presentation, I will
provide an
overview of the ONJ cases reported in
bisphosphonate-treated patients. This will be
followed by a perspective on the
benefit-risk of
bisphosphonates in patients with
metastatic bone
disease by Dr. James Berenson.
Allow me to recognize the
advisors that
are here with us today to help answer
questions
that may come up during the
discussion. It is
important to note that while these
external
191
advisors have been invited by Novartis,
the views
that they express here are their own
views, and not
those of the company.
Dr. Ana Hoff from the M.D. Anderson Cancer
Center is the principal investigator on a
chart
review that is ongoing in cases of ONJ in
bisphosphonate-treated patients. Dr.
James Berenson
from the Institute for Myeloma and Bone Cancer
Research.
Dr. Regina Landesberg,
Assistant Professor
of Oral and Maxillofacial Surgery at
Columbia
University. Dr. Lloyd Fisher, Professor Emeritus
of Biostatistics from the University of
Washington.
Dr.
Salvatore Ruggiero, Chief, Division of Oral and
Maxillofacial Surgery at Long Island
Jewish Medical
Center.
This is an overview of my
presentation.
Importantly, Zometa and Aredia have
delivered
significant benefits for patients with
multiple
myeloma and metastatic disease from solid
tumors,
reducing significant morbidity from the
serious
complications that these patients
experience
192
related to bone involvement from their
tumors.
Novartis has actively examined
cases of
osteonecrosis of the jaw since we
received the
first spontaneous reports in December of
2002.
In spite of this, ONJ remains a
poorly
understood entity. Frequency estimates vary wide,
however, based on available data it
appears to be
infrequent in cancer patients on
bisphosphonates.
Additionally, the anecdotal and
limited
nature of the available data makes it
hard to draw
conclusions about causation or any
difference
between Aredia and Zometa.
Novartis takes reports of ONJ
very
seriously and we are committed to
ensuring patient
safety.
We will do this through conducting further
studies to increase our understanding of
the
condition, communicating our findings,
and
identifying strategies to prevent and
optimally
manage this problem.
The benefits of Zometa and Aredia
in
reducing the significant morbidity
associated with
complications of bone disease in cancer
patients
193
remain highly favorable when considering
the risk
of ONJ.
As the panelists are aware,
metastatic
bone involvement by cancer is a prevalent
condition
and causes serious consequences for
patients with
advanced cancer. The complications of bone
metastases cause considerable morbidity
including
pain, impaired mobility, pathologic
fracture,
spinal cord or nerve compression, and
hypercalcemia
of malignancy.
Zometa and Aredia help people
living with
cancer avoid or delay painful and
debilitating
complications of metastatic bone
disease. As Dr.
Scher noted in her presentation, Aredia
and Zometa
have been both shown to be effective in
the
treatment of bone metastases in multiple
myeloma
and breast cancer.
Zometa has been further shown
to be
effective in prostate cancer, where
Aredia was not
effective, and in other solid tumors,
such as lung,
renal, colorectal, and bladder
cancer. The
benefit-risk of IV bisphosphonates is
well
194
established. Risk of renal impairment is
manageable in most cases by monitoring
creatinine.
Based on this profile, Zometa and
Aredia
have become the standard of care and are
recommended in ASCO guidelines for the
management
of multiple myeloma and metastatic breast
cancer
patients with bone lesions.
I will begin my review with
osteonecrosis
as a general clinical condition before
focusing on
the jaw.
Osteonecrosis is a better known clinical
entity most commonly seen in the
hip. The etiology
and pathogenesis are not well understood.
The common precedent is
impaired blood
supply leading to ischemia of bone. Osteonecrosis
has been associated with a variety of
risk factors,
and is generally felt to be a
multifactorial
process.
Cancer patients are at particular risk of
developing osteonecrosis.
In a search of the general
practice
research database in the UK, the
incidence of
osteonecrosis in cancer patients was 4
times higher
than in the general population.
Coagulopathy is
195
another risk factor as are treatments,
such as
corticosteroids, radiation therapy, and
chemotherapy.
Interestingly, there are
preclinical data
and clinical data to suggest a role for
bisphosphonates in treatment of
osteonecrosis of
long bones. There is a series of 16 patients with
osteonecrosis of the hip who had
improvement after
12 weeks of alendronate by Agarwala, et
al.
Osteonecrosis of the jaw has
been less
frequently described and the incidence in
the
general population is not known. The pathogenesis
is not well understood, although similar
risk
factors to osteonecrosis have been
suggested in the
literature.
It is important to note that
there may be
risk factors that are specific to jaw
bones that
may play a role of pathogenesis of osteonecrosis
of
the jaw.
Exposure to the external environment and
particularly infectious agents through
the teeth is
one issue. In addition, there is repeated trauma
from dental procedures, and lastly, the
oral cavity
196
is an area where the bone is covered by a
relatively thin mucosal layer, which is
subject to
trauma.
ONJ in cancer patients is a
condition of
which there is limited awareness until
recently.
The incidence of ONJ in cancer patients
is unknown.
There were a few case reports
of ONJ in
cancer patients that occurred with
chemotherapy,
and not with bisphosphonates, in the literature
prior to 2003. Another condition,
osteoradionecrosis, related to head and
neck
radiation has been frequently described
with a
reported incidence rate of 8.2 percent.
Novartis received the first
spontaneous
report of ONJ in an IV
bisphosphonate-treated
cancer patient in December 2002. The first series
of such cases were published in 2003 by
oral
surgeons who were treating these
patients.
Since these reports, we have
been
investigating these cases to better
understand this
clinical problem.
There are four data sources
available
197
regarding ONJ that I will briefly review
today -
the Novartis clinical trials, spontaneous
reports
that have been made to Novartis,
literature, and a
retrospective chart review that is
ongoing at M.D.
Anderson.
Before reviewing the data, I
want to point
out that there are significant
limitations in these
data sets which make it difficult to draw
conclusions about many aspects of ONJ.
Controlled clinical trials
offer generally
reliable, quality assured, source
verified data.
The Novartis clinical trials which I will
discuss
were conducted prior to 2001, at a time
when there
was little awareness of ONJ. In addition, the
median follow-up for these trials is
about 5 to 13
months, and we plan to update this
follow-up as
part of the investigation.
The spontaneous report
database, as
expected and as explained well by Dr.
Pamer, may
have incomplete information, as well as
diagnostic
selection and reporting biases.
The existing literature is
mostly case
198
series.
In many cases, the data are incomplete.
In addition, there was the web-based
survey
presented today, which does have some
methodologic
limitations which I will discuss later.
The M.D. Anderson Cancer Center
study is a
retrospective chart review of over 4,000
charts of
patients who have received bisphosphonate
therapy,
looking for cases of ONJ at a single
center. It is
ongoing at the present time.
In addition, there are a number
of issues
which may confound interpretation of all
these data
sets.
The impact of a recent increase in awareness
may affect the numbers and types of
reports
received, the lack of consistency across
these data
sets in terms of case definition, and
there have
been other changes in treatment of
cancers that may
have a possible impact during the same
time period.
Let us look first at our
clinical trials.
We did a retrospective search of the
clinical trial
database to identify cases of ONJ, since
this had
not been identified as any sort of
adverse event
that we noticed during the study conduct.
The lack of clear definition of
ONJ poses
a challenge to identifying these cases in
a
clinical trial database. This shows the process
199
that Novartis uses to identify potential
cases of
ONJ from the clinical trials database and
the
spontaneous reports database.
There is no current MedDRA term
for ONJ,
so in order to screen for potential ONJ
cases,
Novartis used a wide net of 18 MedDRA
terms as
shown.
Cases that resulted from this screening
were medically reviewed to identify cases
of ONJ.
This is the current working
definition
that Novartis uses to identify potential
ONJ cases,
any of the findings shown here with a
suggestion of
maxillofacial area involvement. This is a fairly
broad range of terms because we want to
err on the
conservative side and attempt to capture
as many
cases as we can.
The next two slides show, in
summary,
pivotal trials that have been screened
for ONJ, and
also shows the trials where the ONJ cases
were
identified, because we actually did
identify 6
200
cases consistent with this definition in
this
search.
The first 3 trials are the
placebo-controlled Aredia trials in the
bone
metastases indication. The median duration of
follow-up for these trials was 10 to 18
months. One
case was identified in the multiple
myeloma trial
on an Aredia arm.
007 was a dose-finding study
for Zometa in
bone metastases that had an extension
phase--I am
sorry, that is with Aredia. Two cases of ONJ were
identified in the study in multiple
myeloma
patients, one in the Zometa arm and one
in the
Aredia arm.
036 and 037 were hypercalcemia
malignancy
studies comparing Zometa to Aredia. A single case
was identified in this study on the
Zometa arm.
Study 10, 11, and 39 were the
pivotal bone
metastases studies for Zometa. The median
follow-up was 5 to 14 months in these
studies. 10
was the study that was mentioned, a
non-inferiority
study in breast cancer and myeloma
comparing Zometa
201
to Aredia. A single case was identified in the
Zometa 4 mg arm of the study.
704 was a placebo-controlled
study
evaluating prevention of metastases in
hormone-refractory prostate cancer
without bone
metastases. A single case of possible ONJ was
identified in the Zometa arm.
The 6 cases are for simplicity
displayed
by treatment received. Please note that the dose
groups shown reflected the trials
previously. It
is a variety of trials with different
follow-up
periods, and these are not balanced per
se for
tumor type or indication on bone mets
versus
hypercalcemia, but, in general, if we are
looking
at it, we did not see any cases in 1,347
patients
treated with placebo.
We saw 2 cases of ONJ out of
1,334
patients treated with Aredia, and 4 cases
of ONJ
out of 2,730 patients treated with Zometa. It is
important to note that all of these cases
were
described as non-serious by the
investigators.
The next two slides show
clinical findings
202
in these 6 cases. In the first column, we show the
tumor type, and then the diagnosis, and
the site,
as well as the year that the case
occurred, the
drug, the time to event, risk factors,
and the
severity grade and outcome.
Note that when we look at the
case
description, that 2 cases were called
osteomyelitis
and 1 was aseptic necrosis. Because of lack of
definition, it is really not clear if all
the time
these represent the same clinical entity,
but we
capture all these cases.
Interestingly, there were
clearly cases
similar to ONJ that occurred prior to
2002 in these
clinical trials, one in 1992, 1999, so
they are
rare, but I mean there were cases that
were similar
that did occur.
The 2 Aredia cases shown here
had a time
to onset to ONJ of 28 months and 14
months. The
time to onset of Zometa cases shown here
and on the
following slide were 14, 22, and 22
months.
Also noted is that spectrum of
severity is
seen in these cases. All events were initially
203
graded mild to moderate. Two cases of out of these
6 progressed to Grade 3 and had more
severe
outcomes, such as mandibular fracture and
a
mandibular excision reported on the next
page.
The others were listed as
stable or
unknown at the end of the study.
Case No. 4 is a head and neck
patient who
reportedly developed ONJ 13 days after a
single
dose of Zometa for hypercalcemia
malignancy. These
was no information in the case report on
whether
this patient had radiotherapy, but that
is
something that we are looking into since
it seems
likely given the history of this patient.
We used the same method
described to
search all completed trials for cases of
ONJ. We
did not identify any cases in 3,217
patients
treated with Zometa or any cases in 1,214
patients
treated with Aredia. There are more than 10,000
patients enrolled in ongoing studies, and
to date,
4 cases of ONJ have been reported in
these trials,
all with a dose of 4 mg of Zometa. These cases are
shown on the next slide.
These cases have occurred in 2
patients
with breast cancer, 1 patient with
prostate cancer,
and 1 patient with multiple myeloma. All of these
204
cases reported pre-existing dental
problems
including pre-existing osteomyelitis of
the jaw.
The next data category we will
review is
from the spontaneous reports received by
Novartis.
These are the total number of spontaneous
reports
that Novartis had received as of the
cutoff date
for our report of December 7, 2004, at
the top.
These include both cases that
have been
reported, as well as the reportable cases
from the
literature, and there can be duplication
at times.
As of the December 7th cutoff, there were
610
cases, 119 in Aredia-treated patients,
248 in
Zometa-treated patients, and 243 who were
treated
with both agents, generally Aredia
followed by
Zometa.
Most of these cases have been
reported in
the U.S.
There have been 218 reports in multiple
myeloma patients, and 125 reports in
breast cancer
patients.
To put these numbers into context, there
205
have been 1.9 million patients treated
with Aredia
since 1991 and 1 million patients treated
with
Zometa since 2001.
It should be noted that almost
no Aredia
is currently used in the U.S., having
been replaced
largely by pamidronate generic, and also
the Zometa
use has been increasing recently since
the
approval.
All analyses that are
subsequently
presented are related to the 610
cases. For
completeness, we wanted to include the
current
number of case reports as of February
22nd, which
number 875.
We believe that the increase in
cases is
due to the increased awareness related to
communications on ONJ during the fourth
quarter
last year, such as the Dear Doctor
letter, there
was press coverage. There were reports at
scientific meetings, and we believe that
is what
this is related to, but we have to watch
the
pattern closely.
We looked at all these
cases. This is the
206
610 cases for known risk factors of
osteonecrosis.
While available data can be limited in
many of
these case reports, 74 percent reported
at least 1
risk factor in addition to cancer
diagnosis,
corticosteroids in 38 percent,
chemotherapy in 52
percent, thalidomide in 15 percent.
Twenty-eight cases had
radiotherapy to the
head and neck area, and probably have
osteoradionecrosis instead of this
condition of
ONJ.
Three cases had reported herpesvirus
infection of the maxillofacial area, a
reported
cause of ONJ in non-bisphosphonate
treated patients
in the literature, and 4 percent of
reports had
documented actinomyces infection.
In 50 percent of the cases,
dental events
were reported to precede the diagnosis of
ONJ, with
tooth extraction being the most
common. Many of
the reports were incomplete for this kind
of
information.
This shows the limited information that
is
available from the spontaneous report
database
regarding reported outcomes of ONJ, and
relates
207
this to whether or not the patient
continued
bisphosphonate therapy. I present this although it
really is difficult to draw conclusions
from this
data.
There were only 224 cases which
had
sufficient information. If you look at the last
column, which is the total number of
accessible
cases, about 20 percent of these cases
are reported
as recovered or improved. Forty-one percent are
reported as no change, 8 percent reported
as
deteriorated, with 30 percent being
unknown, a
category which includes recovered with
sequelae.
When we look at the impact of
changes in
bisphosphonate therapy, whether it is
continued or
discontinued, there are really not major
differences in the groups that stand
out. Of those
who continued bisphosphonates, 26 percent
were
reported to have recovered and 14 percent
had
worsened, while for those who had
discontinued
bisphosphonate, 18 percent recovered, and
6 percent
deteriorated.
Unfortunately, this data does
not really
208
allow us to conclude whether continuing
bisphosphonate therapy has an impact on
the course
of ONJ, and further study of this
question will be
needed.
In the spontaneous report
database, it
appears that the mean time of onset,
defined as the
time from initiation of bisphosphonate
therapy
until the onset of ONJ, is longer for
Aredia than
for Zometa.
We believe that a direct
comparison of the
time to onset for Zometa and Aredia is
not feasible
in this data set. Some of the problems have been
talked about already. We don't have a common
definition of ONJ or onset of ONJ.
There is this different pattern
of product
usage. Aredia has been available for a
much longer
time, while Zometa has only been
available for
2001.
The utilization of Aredia has
declined
significantly, while utilization of
Zometa is
increasing, and the recent increase in
awareness
could have accelerated the diagnosis of
ONJ. In
209
addition, concurrent therapy has changed
significantly over time with the
contribution of
this unknown.
I will now comment on
literature reports
of ONJ. This chart summarizes the reports
of ONJ
that have appeared in the literature and
which Dr.
Scher has already mentioned. I just
wanted to
highlight two of these reports.
First, as Dr. Ruggiero has the
largest
series of these cases reported, I wanted
to briefly
mention his findings. He describes 63 cases of
patients who had received bisphosphonate
therapy
and developed osteonecrosis of the jaw.
His results as far as a
description of
these cases are generally consistent with
what I
have reported from the spontaneous report
database
in terms of demographics and reported
risk factors.
The bisphosphonate use reported
in his
series was 57 percent Aredia, 31 percent
Zometa,
and 12 percent others, which included 7
alendronate, and 1 resedronate. The majority of
his cases required surgical removal of
involved
210
bone in this series.
I also wanted to comment on the
study by
Dr. Durie and his colleagues which was
presented
today.
This was a web-based survey, which has
underscored the clinical issue of ONJ in
patients
taking bisphosphonate, and raised a
number of
interesting questions.
There are a number of
methodologic issues
inherent in the type of survey which
limit the
ability to draw conclusions. First, the survey
participants were anonymous and therefore
data
cannot be source verified.
In addition, there are biases
with the
survey methodology. Patients who have an event are
more likely to respond as are patients
with more
recent events, and lastly, as discussed
with our
own post-marketing database, calendar
time is
really a confounding factor because of
the
different durations that Aredia and
Zometa have
been on the market.
The analyses were not adjusted for
calendar time, so caution needs to be
used in
211
interpreting these.
Lastly, I would like to review
early data
from the M.D. Anderson Cancer Center
chart review.
To obtain more information about the
incidence,
clinical features, and natural history of
ONJ,
Novartis is supporting a retrospective
chart review
at M.D. Anderson Cancer Center with Dr.
Ana Hoff as
the principal investigator, and Dr. Hoff
is with us
today.
M.D. Anderson Cancer Center is
a large
institution with access to complete
pharmacy,
clinical and dental records. In this study, all IV
bisphosphonate users have been identified
by the
pharmacy, as well as all charts with a
diagnostic
code consistent with ONJ in the past 10
years,
4,032 charts have been identified.
Dr. Hoff provided us with the
results of
the review of the first 25 percent of the
charts
because we were coming to this meeting
today, and
this was non-random review at this time.
Because of the way that the
charts were
sorted by the pharmacy, patients with the
greatest
212
number of bisphosphonate infusions were
reviewed
first, and, in addition, there were 7
cases that
were reviewed out of sequence because
they were
suspected to have ONJ.
There were 18 cases of ONJ
identified in
the first 963 charts reviewed. Out of 631 patients
with breast cancer, 11 ONJ cases were
identified.
ONJ cases were identified in 6 out of 148
of charts
with multiple myeloma. Another case was
seen in a
medullary thyroid cancer patient.
The time from the first
bisphosphonate to
ONJ was a broad range, from 4 months,
which was an
Aredia-treated patient, to 57 months,
Aredia
followed by Zometa in this case.
In these 18 cases, 4 patients
received
Aredia only, 3 received Zometa only, 1
received
alendronate followed by Zometa, and 10
received
Aredia followed by Zometa.
We look forward to getting
additional
results of this study, and Dr. Hoff may
be able to
comment on her opinions of the findings.
We wanted to look at what is
the frequency
213
of ONJ, what do we know about this right
now. The
background incidence of ONJ in
bisphosphonate-treated patients is not
know, nor is
the incidence in cancer-treated patients
in
general.
The estimates of frequency from
the
various data sets vary significantly, and
as we
have discussed, there are many caveats,
so we
really don't know what the incidence is.
The
spontaneous report database, which is
certainly
underreported, provides a reporting rate
of 0.03
percent if we consider the current
patient numbers.
This is certainly an underestimate.
At the other extreme is the
web-based
survey, which is most likely an
overestimate in
which 6.2 percent reportedly had ONJ.
In the controlled clinical
trials, 0.15
percent of patients had suspected ONJ
cases. The
median follow-up of these trials is 5 to
18 months,
and they were conducted in a time when
there was no
awareness of ONJ.
It is too early to assess the
incidence
214
from the M.D. Anderson study as the
review is not
yet complete, but in the current data,
the rate is
1.9 percent.
ONJ and bisphosphonate-treated
patients is
not yet well understood due to the
significant
limitations in the data sets that are available.
There is no common definition of ONJ in
the various
reports, nor are there common staging or
severity
measures to allow objective evaluation
across
different series of cases. Diagnostic criteria are
not yet established, and information on
the natural
history of disease is not available.
It would be very interesting to
know how
long it takes the clinical picture to
develop, are
there any early changes that precede the
development of ONJ that could guide
prevention
strategies. These are really critical questions.
There is no common treatment
algorithm
either how to manage ONJ or what to do
with the
bisphosphonate therapy, and lastly, we do
not have
an understanding of what factors are
causing this
to happen in a small number of cancer
patients
215
receiving bisphosphonates. Further investigation
is
needed to answer these questions.
Novartis has taken these
reports
seriously, and we have undertaken a
number of
initiatives to better understand ONJ and
to
communicate findings to physicians and
patients.
This slide summarizes activities
since the
first spontaneous reports were
received. Our
activities have focused in three
areas. First, was
to ensure patient safety by making sure
that the
package insert reflected the evolving
information
on this newly-described event. The first update to
the label occurred in August 03, a second
update in
March 04, and the precaution was added in
September
of 2004.
Secondly, it was to learn more
about the
cases.
We have actively followed up on many of the
cases that have come into the spontaneous
report
data set.
We can talk about our methodology, if
you like, and we have been actively
trying to
collect additional information.
This is extremely challenging
as many of
216
the cases are recognized and treated and
reported
by oral surgeons and dentists, while some
of the
patient records with information about
cancer and
therapies are with the oncologists. This is
critical for this type of adverse event.
We have also initiated two
multi-disciplinary advisory boards to
evaluate
these cases and to make some preliminary
recommendations on management. We also initiated
the M.D. Anderson Cancer Center to try
and get more
detailed information on frequency and
characteristics of ONJ.
Our third goal was to communicate
the new
information. We distributed a Dear Doctor letter
describing the label changes to over
17,000
hematologists, oncologists, urologists
who treat
prostate cancer, and oral surgeons.
The results of our advisory
panels have
been distributed as a white paper
beginning at the
ASCO meeting last year, and this
information is
planned to be submitted for publication.
We have also worked with
patient advocacy
217
groups, both to share information and to
discuss
patient education initiatives.
This summarizes some of the key
findings
of the advisory panel that met regarding
the care
of patients with ONJ that are reflected
in the
white paper that has been distributed.
This describes some of the
recommendations
related to diagnosis and treatment of ONJ,
an
important learning from the oral surgeons
who have
cared for these patients is that
aggressive surgery
can often exacerbate the condition and
that
conservative management approaches are
recommended.
Some patients can be managed
with topical
treatments, rinses, and antimicrobial
treatments.
Most critical is to understand
strategies
to prevent ONJ, and there were a number
of
recommendations from the panel. Routine dental
exams were recommended prior to
bisphosphonate
therapy, particularly to identify dental
problems
that should be addressed.
Patient education regarding
good dental
hygiene was considered very important and
good
218
communication between dentists and oral
surgeons
and oncologists was thought to be
essential to
manage these patients.
We have incorporated the recommendations
of this panel into the recent package
insert in the
Precaution section that you are reviewing
today.
Novartis has also reached out
to patient
advocacy groups to share information
about ONJ and
to discuss patient education
initiatives. We
intend to meet regularly with these
groups as they
represent an important way to communicate
with the
patients that have these diseases.
We have developed and made
available a
patient education brochure starting in
August of
04, and have distributed 65,000 copies to
our field
representatives. Physicians and nurses
can use
these materials to educate patients who
are
receiving bisphosphonate therapy.
This brochure describes ONJ,
instructs
patients on good dental hygiene practices
while
undergoing cancer treatment, and urges
patients to
talk to their dentists and their
oncologists if
219
symptoms arise.
We are also currently
implementing
clinical programs to learn more about
ONJ.
Critical as a first step is to develop a
consistent
case definition, staging system, and
severity
assessment. We are in the process of developing
consensus definitions with experts.
In addition, we will obtain
additional
information from our pivotal trials by
attempting
to follow up on completed clinical
studies to see
if any cases of ONJ have occurred beyond
the study
period.
We also plan to capture
specific data on
ONJ in ongoing and planned studies. We plan
several new studies. We are going to do a
retrospective chart review specifically
in myeloma
patients at the University of Arkansas.
We also plan to incorporate ONJ
assessments into trials that have been
planned for
other reasons, to try and get some other
information. We, in particular, are planning a
large randomized prospective study, which
includes
220
breast cancer and myeloma patients, and
will being
the fourth quarter of this year.
In addition, an ONJ assessment
is going to
be incorporated into a study that is
under
discussion and being planned by SWOG in
adjuvant
breast cancer patients, and the details
are under
discussion.
We would also like to initiate
a
prospective study to understand the
natural history
of ONJ in patients newly receiving
bisphosphonates.
We are considering whether we should do a
natural
history study or some sort of registry study.
This shows our large randomized
study that
we are planning to conduct. The objective of this
study is actually to look at therapy with
Zometa
beyond the one-year treatment period, and
looks at
Zometa 4 mg weekly every 3 months and
placebo.
This is a large study in 3,500
patients,
and we are going to incorporate ONJ
assessment in
this study.
This is the SWOG study design. This is a
6,000 patient study randomized to three
arms with
221
different bisphosphonates, and this again
is a very
large study where we could look,
incorporate ONJ
assessment, and get some additional
information.
This just shows the ONJ
surveillance plan
that is incorporated into the SWOG study.
This is our current proposal
for ONJ
monitoring in our clinical trials going
forward.
This is being discussed with
experts. It includes
physical evaluation and dental
evaluation, as well
as imaging with panoramic radiographs,
and we plan
to develop specific CRFs to capture
details of
dental exam and ONJ assessment including
criteria
for staging and severity. We will evaluate at a
minimum of every 6 months.
In conclusion, Zometa and
Aredia are
important medications which have
significant
benefits for patients with multiple
myeloma and
metastatic disease from solid tumors,
reducing the
morbidity from the serious complications
that these
patients have related to bone involvement
of
tumors.
Novartis has actively
investigated cases
222
of ONJ since we received the first
reports, and we
continue to investigate, however, ONJ
remains a
poorly understood entity. Frequency estimates are
variable.
Based on available data, it appears to
be infrequent in cancer patients, but we
need
additional information.
There is insufficient evidence
to
demonstrate a difference between Aredia
and Zometa
in terms of risk of ONJ at this time.
Novartis takes these cases
seriously and
we are committed to ensuring patient
safety, to
increasing our understanding,
communicating our
findings, and identifying strategies to
prevent and
manage this problem.
The clear benefits of Zometa
and Aredia in
reducing the significant morbidity
associated with
complications of bone disease in cancer
patients
remain highly favorable when considering
the risk
of ONJ.
DR. MARTINO: Thank you, Doctor.
I now have a bit of a problem,
which is
that we are going to run overtime, and I
want to
223
give as much time as possible to the
questions and
dealing with the issues amongst the
committee.
Dr. Berenson, where are
you? Now, with
all kindness and love from me to you, can
you
summarize what you are going to say in a
few
moments?
I would be most grateful. Thank
you.
Clinical Benefit of
Bisphosphonates in
Cancer Patients with Metastatic
Bone Disease
DR. BERENSON: I guess that is why my
mother made me take impromptu speech in
high
school.
Let me be brief. What I want to do is
summarize the benefit of bisphosphonates
for cancer
patients with metastatic bone disease.
This is an extremely common
problem. More
than 500,000 Americans are afflicted with
it. Most
myeloma patients develop metastatic bone
disease or
myelomatous bone disease, most patients
with
breast, prostate, and a significant number
of lung
cancer, as well.
The median survival importantly
of these
patients is measured in years, unlike
other
224
metastatic sites in which patients succumb
often
within weeks to months. These have major clinical
consequences, not only for the patient,
the
families, but society in general, and the
reason
for that is shown here.
That is because these lead to
consequences, and in the top four, in
yellow, you
see where they care considered
skeletal-related
events from the studies that have been
done by
Novartis with Aredia and Zometa.
These are the placebo
arms. Commonly,
patients fracture. These are the number of
patients or percentage of patients per
year who
develop these complications. Less commonly they
develop cord compression of collapse,
often leading
to the requirement for radiotherapy or
surgery to
bone, hypercalcemia less common, bone
pain frequent
before bisphosphonates, often leading to
the use of
analgesics with quality of life effects,
of course,
ultimately impacting the patient's
survival.
Now, here is the overall
results of
bisphosphonates that have been done. First, in the
225
nineties, that we did with Aredia, that
is, the
myeloma trial showing a marked reduction,
as you
see, in both the percentage of patients
with an
event by 21 percent, the endpoint, and
more
impressive on the right side is halving
from 2 to 1
of the number of events per year.
Similar data from the breast cancer data
led by Hortobagyi shows a nice reduction
in both
the percentage of patients with an event
and about
a third reduction in the number of events
per year.
As one can see in the trials
that have
been similarly conducted with prostate
cancer,
Kohno, a recent Japanese study, and Lee
Rosen's
study, marked reductions not only in the
percentage
of patients with an event, but impressive
and
important, the number of events per year
is halved,
from a third to a half, huge reductions
when one
thinks about the 500,000 of Americans who
have this
problem.
Now, the only head-to-head
comparison of
Zometa and Aredia, which led to the
approval of
this drug, as you know, for breast and
myeloma,
226
this was a non-inferiority comparison
trial, of
course, but one can see the four major
endpoints
all favored Zometa, less patients with an
event, a
delay in time to first event, reducing
the number
of events per year by approximately a
third, and on
the right side, the multiple event
analysis taking
into account not only the time to first
event, but
time between subsequent events, a 16
percent
relative risk reduction and statistically
significant in favor of Zometa.
So, what does this all
mean? Well, first
of all, it means that Aredia has been
shown to
definitively reduce skeletal
complications in
breast and cancer patients with lytic
disease only.
Two studies showed it to be
ineffective in
prostate cancer that were randomized I
did not
mention.
It has not been evaluated in other tumor
types.
In addition to breast cancer and myeloma,
Zometa has been shown to dramatically
reduce the
skeletal complications in patients with
prostate
cancer, that is, metastatic to bone, as
well as
other solid tumors that are metastatic to
bone.
Data I did not present, these
drugs have
been shown to markedly reduce bone pain
and the
requirement for analgesics, and, indeed,
in trials
227
done with both Zometa and in the past
with Aredia,
preventing the deterioration in the
quality of
life, most important to our patients with
metastatic cancer to bone.
In our own experience, we have
had 6 cases
of ONJ, and by the way, we have had more
than that
number of patients who were referring to
our oral
surgeon with a presumptive diagnosis from
the
dentist who did not have it.
There has been an important
range of
severity.
Three patients required only
intermittent antibiotics were on Aredia
and Zometa
in one case, and Zometa only in the other
two.
They remain on ongoing bisphosphonate
treatment,
and their symptoms have all improved.
One patient was only diagnosed
last month.
She remains on treatment, her symptoms
largely
resolved with several weeks of
clarithromycin
orally.
Two other patients, one on Aredia followed
228
by Zometa, one on long-term Zometa on a
clinical
trial initially, discontinued
bisphosphonates
secondary to significant effects on
chewing.
Importantly, both of these patients have
markedly
improved by being off the bisphosphonate
and are
chewing normally in one case, and almost
normally
in the other.
Equally importantly is the
bottom bullet,
the status of these patients'
myeloma. One of
these patients has had a skeletal-related
event, 3
are in long-term complete remission, 1
following a
transplant, 1 simply on VAD alone, and 1
on
thalidomide alone.
One is in near complete
remission, and
impressive to me is the last
sub-bullet. Two
patients on long-term therapy are still
indolent,
and both patients have received no other
treatment,
and, in fact, 1 patient had a 40 percent
reduction
in M-protein, which is ongoing 5 years
later.
So, skeletal complications have
profound
effects on the lives of patients with
metastatic
bone.
We have seen data that shows that the IV
229
bisphosphonates markedly reduce the risk
of bony
complications.
Both then number of events per
year are
reduced by about a third to a half, and
the percent
of patients with any event by 15 to 40
percent.
These drugs have profoundly reduced bone
pain, the
requirement for pain medication, and
prevented the
deterioration in the quality of life.
As you have seen, patients
receiving IV
bisphosphonates may infrequently develop
ONJ. What
the frequency is, we don't know. We have seen a
range of numbers I put up here. Equally important
is the severity, it varies markedly, and
in all of
our cases, it has improved even on
patients who
continue on therapy with oral antibiotics
and
Peridex washes.
Thus, the risk of ONJ is a
minor one, it
is rarely clinically significant in our
own
practice compared with the major problems
that
would result if patients did not continue
these
important medications. That is the high risk of
fracture you have seen that is reduced,
the risk of
230
cord compression, the requirement for
radiotherapy
or surgery to bone.
Thus, the benefits, the
reduction in
fractures, the requirement for
radiotherapy,
reduction in bone pain, and ultimately
the impact
on quality of life far outweigh the
putative small
risk of ONJ and the renal deterioration
that
infrequently occurs, and with good
management, is
even less frequent, and I will stop
there. Thank
you.
DR. MARTINO: Thank you, Doctor, I most
appreciate your succinctness.
Open Public Hearing
The next part is the public
portion of our
program.
There are several of you that have asked
to address this committee. The microphone you are
going to use is the one that is in the
center of
the room, and as you get ready for that,
I need to
read a statement to you that relates to
your
presentations.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
231
information gathering and
decisionmaking. To
ensure such transparency at the public
hearing
session of the Advisory Committee
meeting, FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, the FDA
encourages you,
the open public hearing speaker, at the
beginning
of your written or oral statement to
advise the
committee of any financial relationship
that you
may have with the sponsor, its product,
and, if
known, its direct competitors.
For example, this financial
information
may include the sponsor's payment of your
travel,
lodging, or other expenses in connection
with your
attendance at today's meeting.
Likewise, the FDA encourages
you at the
beginning of your statement to advise the
committee
if you do not have any such financial
relationship.
If you choose not to address this issue
of
financial relationship at the beginning
of your
statement, it will not preclude you from
speaking.
MS. CLIFFORD: Felice.
DR. O'RYAN: Felice O'Ryan. I am an oral
and maxillofacial surgeon at Kaiser
Permanente in
Northern California, and after hearing in
2003, Dr.
232
Sal Ruggiero's wonderful presentation
about
osteonecrosis in bisphosphonate patients,
I finally
found what I thought was at least some
sort of
beginning answer to what I had been
seeing.
In Kaiser Permanente, we have
3.2 million
members in Northern California, and 4
million
members in Southern California,
therefore, we have
a huge and well-documented database.
My colleagues in Southern
California have
also noticed some of the problems we have
been
seeing and after looking at some of the
clinical
problems, I am looking to you today to
present some
cases, show you the spectrum. I do not consider
these problems minor or insignificant,
nor do my
patients, and to ask for guidance.
I also feel that the FDA and
Novartis has
done a very poor job of informing people
about this
potential risk. I have informed our
oncologists at
Kaiser Permanente via e-mails and
attached clinical
233
photos about the risk of this.
Unfortunately, the oncologists
are not
particularly comfortable doing oral
exams, and so
some of this has been missed.
I won't go through the
pathophysiology, I
think that is pretty well known to
people. I am
just going to show you the spectrum of
cases that I
see from what I would consider minor and
insignificant.
This is a 65-year-old woman
with breast
cancer. She has been on--all my patients
have been
on, first, Aredia, followed by
Zometa. The
earliest has been 6 months after the
initiation of
Zometa treatment.
I have at least 30 patients,
and these are
unsolicited patients, in other words,
patients that
have been referred to me with this
complaint.
She did undergo a dental
extraction and on
your right you can see that she has
teeth, and just
behind the teeth, around the mucosa, is a
small
bone defect that has been chronically
present, not
responsive to oral antibiotic therapy,
nor oral
234
rinses.
This is another patient of
mine, a
68-year-old male, multiple myeloma, been
on both
Aredia and Zometa. He does have some bad teeth, I
admit it.
However, unfortunately, you
can't see this
particularly well. The necrotic areas in his
mandible are up on the right corner and
look like
some food debris. That is not food, that's his
jaw.
These are how my patients have all begun.
The tissue on the lingual
surface of the
mandible initially sloughs off, and then,
like the
jaw is on fire, it continues, at least in
my small
patient group, from the back end of the
mandible up
to the front end, and can involve teeth.
The majority of my patients
have not had
dental extractions, dental trauma, dental
treatment
before presenting.
Again, this is not responsive
to
antibiotics or local oral therapy.
This case concerns me the very
most. She
is a 60-year-old delightful woman with
multiple
235
myeloma, been on both Aredia and Zometa,
thalidomide, and, of course, all these
patients
have been on corticosteroids.
She came to me with a small
lesion in her
mandible that began as the size of maybe
a small
split pea in the back. What you are looking at is
6 months or progression. This is her
mandible.
This is dead bone. She has had a draining fistula
on the outside of her face that now she
has been--I
have had her on a PIC line, I have had
for
hyperbaric oxygen.
It is continuing to
spread. I have
nothing to offer her. I have no treatment. I
can't resect this because the rest of the
bone is
dead and there is nothing normal to
resect to. She
is looking at a possible free fibula
flap, which is
a 20-hour operation, and a really hard
hit for
these people who are already medically
compromised.
So, I don't think anybody can
stand here
and tell me that that is an insignificant
problem.
These patients are in pain, they smell
bad, they
can't eat, and nothing helps fix them.
So, the question about tooth
extraction,
poor oral hygiene and possible associated
medications are totally legitimate. I may have a
236
unique subset of patients who have not
had dental
extractions in the majority of the
cases. Poor
oral hygiene, possibly, but again many of
my
patients are edentulous, so poor oral
hygiene or
tooth extraction has nothing to do with
it.
Associated therapies, you know,
possibly.
We don't know. All I can say is that I have never
seen this until recently.
What is the prevalence? Who do we prevent
it, and what do I do to treat these
patients? I
think we have databases that are
available to us to
look at.
We are just in the process of looking
into this at Kaiser Permanente.
I don't know the prevention,
and I
certainly don't know the treatment, but I
would
love to know what the treatment could
be. We have
had our patients discontinue the
bisphosphonates.
I have not had a single lesion heal. I have not
seen a single lesion regress. I have only seen
237
them become worse.
So, I don't know if I have a
unique subset
of patients or what.
Thank you.
MS. CLIFFORD: The next speaker is Scott
Santarella and Bruce Holmberg.
MR. SANTARELLA: Good afternoon. My name
is Scott Santarella. I am the Executive Director
of the Multiple Myeloma Research
Foundation located
in New Canaan, Connecticut. Personally, I receive
no financial support from Novartis,
however, our
organization has received unrestricted
educational
grants for educational programs relative
to
multiple myeloma disease.
The MMRF is a nationally
recognized
501(c)(3) nonprofit. We are the world's largest
nonprofit funder of myeloma research, and
I thank
you for providing me a few moments to
speak today.
On behalf of the nearly 200,000
patients,
family members, and caregivers associated
with our
organization and the issue of
osteonecrosis of the
jaw and bisphosphonate use, I would like
to just
238
say a few words.
As an organization that devotes
80 percent
of the funds we raise to support research
efforts,
we have access to and committed
partnerships with
the world's leading myeloma experts.
In addition, our secondary
focus of
providing the myeloma community with
educational
and informational programs relative to
the latest
treatment options and therapies, we have
become a
well-respected resource with more than
500,000
visitors to our website annually.
In addition, our focus for the
last eight
years has been providing patients,
clinicians,
caregivers, and nurses with the most current
information on treatment options and
clinical
trials available, as well as educating
patients on
supportive care therapy like the use of
bisphosphonates in treating multiple
myeloma.
With this information as a
backdrop, it
has been our experience in working with
the
hundreds of the world's leading myeloma
researchers
and local hematologists, as well as the
tens of
239
thousands of patients who rely on
bisphosphonates
in the treatment of bone disease suffered
by those
patients, that bisphosphonates are
considered an
essential part of supportive care for this
disease
community.
As an organization, we feel the
relatively
small number of cases of osteonecrosis of
the jaw,
although worthy of note and attention,
are minimal
in comparison to the benefits
bisphosphonates
provide the majority of the patients.
In addition, it has been our
experience
that the information available on
bisphosphonates
use provided by companies like Novartis
have always
been presented in a very detailed format
with
explanation of dosing levels, as well as
preventative measures one would undertake
to avoid
possible risk factors associated with the
use of
these compounds.
It is our hope that ODAC will
undertake a
complete review of not just the incidence
of
osteonecrosis of the jaw, but the overall
research,
both historically and currently, that
shows the
240
treatment value and benefit of
bisphosphonates in
the care of multiple myeloma patients, as
well as
other cancer patients relying on these
compounds to
help them in the treatment of their
disease, and
recognize it as an essential to their
care and
quality of life.
MR. HOLMBERG: Good afternoon. My name is
Bruce Holmberg. I have absolutely no financial
connection with Novartis.
I live nearby in Rockville and
I am
multiple myeloma patient, diagnosed with
Stage I
IgA multiple myeloma in May of 2000 when
I was 61
years old. I am treated here at the National Naval
Medical Center in Bethesda.
I am here today to give you a
brief
experience or a brief view of my
experiences with
bisphosphonates as it relates to my
multiple
myeloma.
When I was diagnosed, like so
many, I had
never heard of this blood cancer. My only signs
were anemia, and at the results of my
first
skeletal survey, which occurred a month
after I was
241
diagnosed, showed only some slight
lesions in my
skull.
When I heard my diagnosis, I
asked the
hematologist two questions, what was my
prognosis
and what is my treatment. To the first, he said,
"Well, statistically, three to five
years, but you
may be one of these patients who goes on
for many,
many years."
To the second, he said,
"There is none,
your disease is not bad enough yet to
treat, and we
just watch your disease as it progresses
until the
treatment is less harmful to you than the
cancer,
then, we do something."
That answer thoroughly baffled
me until I
went home and researched multiple myeloma
on the
website.
What I saw were terms like immune system
failure, kidney failure, incurable,
fatal, and bone
destruction.
The treatments were chemo and
stem cell
transplants primarily, and neither did
more than
buy much time, or buy time, and not much
at that.
I changed doctors to one who
was more
242
proactive. At my second appointment, he
related a
conversation he had with a prominent
myeloma
researcher at the association, at a
recent Ash
meeting, where he had asked if Aredia
could be
given as a prophylactic before the onset
of bone
destruction to suppress the effects of
the myeloma.
The answer was yes, that there
was a good
possibility that Aredia had a suppressive
effect on
the development of the myeloma cells
themselves.
I began a monthly Aredia
treatment
immediately. My disease progressed very slowly, so
that Aredia, and then Zometa, when it
became
available, and I did make that switch,
was my only
treatment for three years.
In 2003, it got bad enough to
warrant the
addition of low-dose thalidomide and
later the
steroid dexamethasone. Thalidomide and
Zometa alone
helped, but I had an immediately and near
complete
response to these combined treatments of
Zometa,
thalidomide, and dex.
While I know this treatment is
likely
temporary, that sooner or later the
cancer will
243
mutate around the treatment, I am
incredibly
grateful for this respite.
My quality of life is really
important to
me.
I am very physically active. I
hike, bike,
work out daily, ski. I am still an active
patrolling member of the National Ski
Patrol. So,
bone health is at the very top of my
list.
Despite the progress of my
disease, my
bone structure remains as it was when I
was
diagnosed, only slight skull lesions that
have
never gotten any worse, probably damage
that was
done before I was diagnosed and started
on
bisphosphonates.
My hematologist, my dentist,
and I
understand the potential issues with jaw
osteonecrosis. If I need a dental procedure that
might pose a risk, we plan to suspend the
use of
Zometa for a period in advance of the
procedure.
I acknowledge that as more
information
becomes available, more precautions may
be
necessary, but the benefits of
bisphosphonates to
us multiple myeloma patients
significantly outweigh
244
any known down sides.
Let me add one more point. None of the
treatment options we myeloma patients
have
available are without side effects, some
of them
serious, but we take them and we tolerate
the side
effects and mitigate them when we can because
the
alternative is so unsatisfactory.
I have no side effects or have
had no side
effects in the five years of taking
Aredia and now
Zometa, no bone pain, no kidney issues,
and no jaw
problems.
I urge you to weigh all of the benefits,
as well as the potential risks as you
make your
deliberations.
Thank you.
MS. CLIFFORD: Thank you, Mr. Holmberg.
Our next speaker is Michael Katz.
MR. KATZ: My name is Michael Katz and I
am a Vice President of the International
Myeloma
Foundation. This is an uncompensated volunteer
position.
The organization receives unrestricted
educational grants from Novartis, I
receive none,
245
no compensation from either the IMF or
Novartis,
and I have paid my own way to come to
this meeting.
As an advocate, I am in
constant contact
with patients and caregivers with
multiple myeloma.
With the IMF, I have helped conduct over
two dozen
patient and family seminars across the
country, I
lead two in-person myeloma support
groups, and
moderate an on-line myeloma-specific
listserv with
over 1,300 members, hosted by the
Association of
Cancer On-Line Resources.
I also do phone counseling as
part of the
IMF hot line. I am here today to speak to you as a
patient.
I was diagnosed with multiple myeloma in
1990.
Over the past 15 years, the disease has
relentlessly attacked my bones, causing
serious
damage to my pelvis, both hips, multiple
ribs, two
vertebrae, my skull, and my shoulders.
I have had various systemic
therapies
including steroids, Melphalen,
thalidomide, 8
courses of radiation including radiation
therapy to
the jaw.
I began taking Aredia in January of 1995,
over 10 years ago, and I have since had
over 120
246
infusions.
As such, I am very concerned
about the
rapid rise in reports of osteonecrosis of
the jaw
in patients with myeloma and other
cancers. I
applaud the FDA and ODAC for taking the
initiative
to have a public dialogue on this very
serious
safety issue.
Even with the potential risk of
ONJ,
bisphosphonates are an important part of
therapy in
minimizing bone damage to patients with
myeloma and
other cancers that threaten the bone.
ONJ is preferable to a
collapsed vertebrae
or broken femurs. It is important that
bisphosphonates are made available to
patients who
can benefit from them, but we also need
to make
sure that we can protect our bones from
destruction
by cancer, and at the same time, minimize
the risk
that we will develop serious problems
like ONJ.
Dr. Durie and I had met with
representatives of Novartis at last
spring's ASCO
meeting to understand what could be done
to better
understand this issue and provide more
practical
247
information to both patients and
physicians.
The idea for the web-based
survey that was
discussed earlier initially came up at
this
meeting.
As Dr. Durie said, we were able
to recruit
over 1,200 respondents within 30 days.
Participants completed an extensive
survey
detailing diagnosis, treatment history,
dental care
habits, and any dental issues including
both
explicit diagnosis of ONJ, as well as
symptoms that
would be indicative of undiagnosed ONJ.
The results of this survey,
which Dr.
Durie presented earlier, were dramatic,
showing
increased time dependent risk associated
with
Aredia and Zometa, and no statistical
association
with any of the other treatments reported
including
steroids, thalidomide, or Valcade,
radiation or
alkylating agents.
As Dr. Durie stated, the time
dependent
risk associated with Zometa was
dramatically higher
than that associated with Aredia. People this
morning and outside this forum have
characterized
248
osteonecrosis of the jaw as a
long-standing issue
in oncology patients. They call it rare. They
raise issues about the condition being
imprecisely
defined and standardized criteria for
diagnosis not
being established.
They cite the many other risk
factors that
could contribute to or cause the
problem. The fact
remains, though, that almost all of these
risk
factors have been facts of life for
decades in
myeloma and other cancers. Why, one must ask, has
this problem become so much more
pronounced in
these few short years.
They also point out the
limitations of
anonymous surveys and of patients and
caregivers
self-reporting medical information. Are there
limitations with this type of survey? Certainly,
there are. Indisputably, prospective clinical
trials are the gold standard for efficacy
and
safety data.
Having said all of this,
though, I must
ask if these same people had cancer and
had to make
the decision to put the IV in their arm
every month
249
and hang that bag of bisphosphonates, I
wonder if
they would be so dismissive of data
provided by
1,200 concerned fellow patients.
Would they ignore this data and
wait two,
three, four, or more years until these
studies
could be completed and better data is
available? I
doubt it.
It is clear that osteonecrosis of the jaw
is a problem that has mushroomed in the
past few
years.
To quote Dr. Robert Kyle of the Mayo
Clinic, who chairs the IMF Scientific
Advisory
Board, I quote, "In my 40-plus years
of caring for
patients with multiple myeloma, I had not
seen or
heard of osteonecrosis of the jaw in this
disease
until one to two years ago."
Prospective trials take years
to design
and execute. When dealing with serious safety
issues like ONJ, we cannot afford to wait
years.
These trials should be done, but we need
to use the
data that we can acquire more quickly via
retrospective studies and surveys to help
patients
and their doctors make better decisions
today.
I applaud you for allowing us
to share
this data with the scientific community
and the
public, and I applaud you for daring to
ask the
250
question how can we use this data to help
patients
and physicians make better decisions
today while we
work to learn more tomorrow.
ONJ is not a stroke, it is not
a heart
attack, it is seldom life-threatening
although I
must say I did meet a woman last month at
our
patient seminar in Dallas whose husband
died of
complications resulting from his ONJ.
More commonly, though, ONJ is a
painful
condition that can destroy a cancer
patient's
quality of life. It is painful, the patient's
teeth fall out. It can interfere with speech, make
eating difficult. It can also prevent patients
from receiving life-saving treatments like
transplants.
Yet, bisphosphonates are proven
to prevent
or lessen the severity of cancer-induced
bone
damage and must remain available to the
patients
who need them. Having said all of this, what would
251
and my fellow patients ask of the FDA and
Novartis?
First, please be more proactive
in getting
the word out to patients, caregivers,
hematologists, oral surgeons, and, for
God sakes,
the regular dentist, because those are
the people
that are pulling teeth out and triggering
this
condition.
The labeling changes, the white
papers,
the Dear Doctor letters, they are all
steps in the
right direction, but they don't go far
enough in
terms of audience or message.
Second, please provide answers
as soon as
possible, and I know these are tough
questions, to
the following four questions:
1. If patients have been on Aredia or
Zometa for a long period of time, is
there a point
at which they should consider decreasing
the
treatment frequency or dosage?
2. If there is a dental problem that
requires invasive surgery, to what extent
can the
risk of ONJ be reduced by stopping or
tapering
Aredia or Zometa therapy?
3. Given the risks, under what
circumstances is prophylactic use of
Aredia
justified?
252
4. Lastly, given the evidence of
increased risk of ONJ and kidney damage,
and the
lack of evidence of any incremental
benefit of one
drug over the other, why should any myeloma patient
be given Zometa as opposed to Aredia?
One last thought. In the preapproval
setting, the possibility of harm must be
excluded
by proving that a drug is safe. Drugs are guilty
until proven innocent. In the post-marketing
setting, where we now find ourselves with
these
drugs, we change our tune, requiring
proof of harm
rather than proof of safety. Drugs are innocent
until proven guilty.
As a patient taking these
drugs, I find
this difficult to understand.
I than you for the opportunity
to speak,
and I thank you for your diligence in
investigating
this matter.
MS. CLIFFORD:
Thank you, Mr. Katz.
Ron Rogers?
MR. ROGERS: I, too, have multiple
myeloma.
It was discovered in 1999.
Approximately
two months later, I went on Zometa. I have
continued on Zometa to this day, and live
an
extremely active lifestyle, skiing,
writing,
253
hiking, hunting, fishing.
In January of 04, I was
diagnosed with
osteonecrosis. With antibiotics, it had cleared up
within approximately six months, and I
still am on
Zometa, and I am thankful to be able to
have the
kind of lifestyle I have.
Thank you.
DR. MARTINO: The Committee is grateful to
all of you who have spoken, and as
always, you have
a way of putting all of this in the right
context
for those of us that sit here. I am personally
grateful to each of you for this
morning's
contribution.
Committee Discussion
DR. MARTINO: The next portion and the
final portion of this meeting is actually
the
254
discussion amongst the panel. There really are
three sets of questions that I want to
focus you
on, and the time is short, so again,
please be
succinct, I want your thoughts and not
your
ramblings.
The first question really relates
to given
that we recognize that there is a
potential problem
here, have we appropriately informed the
necessary
people.
The second question relates to
do we know
what to do, either in terms of preventing
this
problem or in terms of treating it once
it occurs.
Thirdly, are there additional
studies that
need to be done.
I would like to address the
first question
first, however. Have we informed the right people
and in the proper manner? To that, can I ask the
company to basically, briefly, summarize
what they
have done in terms of informing and who
have they
informed.
DR. YOUNG: I am going to invite my
colleague, Peter Tarassoff, to the stand
to talk
255
about the communication efforts of
Novartis.
DR. TARASSOFF: Good afternoon. My name
is Peter Tarassoff. I am with Novartis Oncology,
Medical Information and
Communication. I would
just like to briefly summarize the steps
that we
have taken to bring this matter to the
attention of
the patient groups.
We maintain an ongoing
dialogue, as Dr.
Young had indicated, with a number of
patient
advocacy groups. In May of 2004, we hosted a
meeting hear our offices in New Jersey to
which we
invited a number of representative
patient groups
to come and listen to the discussion that
we had in
terms of what we knew about the topic of
osteonecrosis of the jaw.
Again, we had further meetings
with
representatives of additional groups at
the Ash
Meeting in San Diego in December 2004,
and provided
further updates on this information.
At the time that the Dear
Doctor letter
was published by Novartis in September
2004, we did
publish this patient brochure that had
several
256
topics of pertinent information that
would be
useful to patients.
We have distributed, as Dr.
Young had
indicated, approximately 55,000 copies of
this
brochure to our sales representatives to
give to
the health care professionals that they
see during
the course of their daily activities, and
we have
been very vigorous in instructing them to
be
proactive, to be sure that offices where
Zometa is
given, that this particular information
was given
out.
It contains information for
patients to be
able to recognize the signs and symptoms
of
osteonecrosis. It calls to their attention the
fact that there are certain items of
dental hygiene
that they need to be aware of, and
thirdly, it
provides them information that they
should share
with their dental professionals in terms
of their
cancer treatment and things that a dental
professional should be aware of.
We have this information also
available on
the Novartis U.S. Zometa website. This information
257
is here.
A number of the patient advocacy groups,
we understand also have this information
on their
website, so we try to use as much of the
new IT
technology that we have available to us
to make
this information available to greater
numbers of
patients.
This is the white paper that
represents
the two advisory board meetings that we
held in
December 2003 and again in March of 2004,
to try to
put together in a succinct format information
that
could be made available to health care
professionals, to bring to their
attention this
topic of osteonecrosis, what might be
able to be
done to prevent it, what should be done
in terms of
treatment.
We have distributed this initially at
the
ASCO meeting in New Orleans in June
2004. Through
our offices, we have distributed an
additional
3,000 copies that have gone out to health
care
professionals who have questions about
the topic of
ONJ.
We provided them this information, as well as
a copy of the Dear Doctor letter.
So, we have tried to look at a
number of
different avenues by which we can share
this
information with both patient communities
and also
258
with the oncology and dental communities.
We do have a manuscript that
stems from
this white paper that is now undergoing final
review, and our plan for that is to
submit it to
journals that will be read by
oncologists, as well
as health care providers in the dental
fields.
Thank you.
DR. MARTINO: A question on the Dear
Doctor letter. I am assuming those are sent to
oncologists, or are they sent more
broadly? I am
particularly concerned with the dental
professionals.
DR. TARASSOFF: The 17,000 copies,
slightly more than 17,000 copies of the
Dear Doctor
letter were sent out to hematologists,
oncologists,
urologists, and oral surgeons in the ADA
database.
We have considered also the idea of
sending it to
dentists, and that is something that is under
consideration.
DR. MARTINO: That would strike me as a
key group to whom this should be
disseminated since
they are more likely to be the ones who
see
patients for these problems.
Dr. Brawley.
DR. BRAWLEY: I am interested in what is
259
being done in terms of promotion of
Aredia and
Zometa for usage right now. For a while after
Zometa's approval, it was sort of like a
freight
train moving toward it being malpractice
for those
of us who take care of patients who have
metastatic
disease or the threat of metastatic
disease, to not
put them on Zometa.
I am wondering what now is the company
doing in terms of promoting the usage of
both
Aredia and Zometa.
DR. YOUNG: I am going to invite our
colleague, Dr. Deborah Dunsire, to speak
about the
promotion of Zometa and Aredia.
DR. DUNSIRE: Good afternoon. My name is
Dr. Deborah Dunsire from Novartis.
Zometa is actively promoted by
the
260
Novartis Oncology Sales Forces at this
time.
Aredia is no longer promoted. It has been
generically available since 2001, and at
the
present time, there is practically zero
Aredia
utilization. Any pamidronate use has moved over to
generic pamidronate, and the promotion is
always
within the FDA label and within the OIG
guidelines.
If there is anything further I
can
clarify, please ask.
DR. BRAWLEY: I am not satisfied with the
answer, but I don't know exactly how to
ask for a
better answer. You are still promoting Zometa. I
mean literally in Atlanta, virtually
everyone with
metastatic disease was donating $6,000 to
Novartis
for Zometa treatment, and that may be an
overusage
of the drug.
So, I will just leave it at
that. I don't
know if you want to respond to that or
just leave
it as a comment.
DR. DUNSIRE: I think that the drug is
promoted for patients with bone
metastasis because
of the benefits that it provides.
DR. MARTINO: Dr. Perry.
DR. PERRY: I have a comment and a
suggestion, Dr. Pazdur. Richard, this seems to me
261
to be a great topic for dissemination
through the
CCOP [ph] mechanism, and perhaps a great
research
project for them to get cancer control
credits
perhaps by first making people, their
patient
populations aware of the potential
problem, and
then when we get a little bit--hopefully,
a whole
lot smarter, knowing how to identify and
treat it
better, then a treatment program.
I take it you still talk to
those people
and can convey that suggestion.
DR. PAZDUR: I think that is an excellent
idea and we will bring it back and
discuss it with
the CCOP people, but I think that is even
an area
to look at, even a registry potentially
incorporating their practices in, because
it does
represent perhaps even a more real world
type of
usage of these drugs outside of a cancer
center,
which may have its own peculiarities
about it, as
the M.D. Anderson data is doing.
DR. MARTINO: Dr. Levine.
DR. LEVINE: Several comments. First of
all, one of my problems is that the
patients who
are being educated are those who are
perhaps more
involved, i.e., they are members of
support groups,
they are on the Internet, and so forth,
and I am
262
worried about the regular patients out
there who
may not be involved in that sense.
I am not sure, so I will defer
and ask
you, but I believe the company markets
this on
television directly to the patients, and
if that is
true, then, I would absolutely ask that
you market
something else about this. If you don't market, I
would still do that. It needs to go to the general
population.
The reason I feel strongly is
that I am
worried that simply by stopping the
product for a
month or two, that is not really going to
help as
far as what to do, and what you have to
do is
prior, I guess, some of the sense I am
getting, is
that you may want to advise patients to
take care
of dental work prior to ever starting
these
263
products.
So, you have to do it in a
proactive way.
I also agree with what has been said as
far as
educating very carefully the dentists,
and when I
go into the dentist, the technician says
to me, you
know, any change in your medical health,
but I
would want the technician to be saying to
me, have
you taken these drugs, and list them
right there.
The second thing, and I have to go, so I
am not going to answer this properly in
order, but
one of the questions that really needs to
be
answered here is what is the appropriate
duration
of use of these drugs, is there, in fact,
a moment
where the risk outweighs the benefit, and
I don't
think there are data to address the
question. That
would be an extremely important one.
There was a New England Journal
article,
not about this at all, but several years
ago, using
one of these products for osteoporosis,
and I think
the finding was that one dose a year was
as good as
once a month or whatever it is. So, those kinds of
questions really have to be addressed.
DR. YOUNG: I would first like Dr. Deborah
Dunsire to address the question about
promotion,
and then I will address your question
about longer
264
term duration of therapy.
DR. DUNSIRE: Deborah Dunsire from
Novartis clarifying that Zometa is not
promoted on
television at all, and that the
direct-to-patient
and outreach to the regular patient, who
isn't
engaged in the Internet, is really
through their
physician.
It is the only way we can get
to them, and
that was the purpose of the patient
brochure around
osteonecrosis of the jaw, and in our
regular
patient education materials, which can be
given to
a patient when they start Zometa, we have
also
added information on osteonecrosis of the
jaw,
hoping and encouraging all the
professionals,
physicians and nurses, who are in contact
with
patients, to give this to the patient, so
that they
can become aware. Thank you.
DR. YOUNG: I just wanted to add that I
was kind of rushed at the end of my
presentation,
265
but one of the studies that we are
undertaking,
which we have actually been in
discussions about
the FDA, is a study that takes patients
who have
been on treatment for a year with
multiple myeloma
and metastatic breast cancer, and then
randomizes
them to either Zometa in the label dose
very 3
months or placebo, and that is really a
large study
that is designed to get at this question
about
demonstrating continued benefit and safety
of
therapy, and also it is a good setting to
be able
to monitor for osteonecrosis of the jaw.
DR. MARTINO: Dr. D'Agostino.
DR. D'AGOSTINO: I have a couple of
comments and I am going to jump from the
first and
the third question. I think in the first question,
in terms of the information being sent
out, I think
there is a lot of information. The program seems
to be moving along well.
My concern is, is there an
evaluation
component, how do you know you are
actually
reaching anybody, and especially the
patient and
the oral surgeon, are they thinking this
way, and
266
they get a lot of information, they may just chuck
it in the pail, I don't know.
So, I think there should be,
and there may
be, but I think there should be an
evaluation
component that the FDA may want to insist
on.
In terms of the clinical
trials, I think
the registry idea is good, and I think
the clinical
trial, they have got ongoing clinical
trials, which
sound very nice. My concern there is are they long
enough and are they big enough to pick up
the
safety issue if they are designed for
other things.
So, I think if they embed this
question
within a clinical trial, it has to have
some hope
of getting at an answer to this particular
problem.
DR. MARTINO: Dr. Hussain.
DR. HUSSAIN: I think some of the issues I
wanted to raise was raised by Dr. Levine,
but I
want to reiterate the issue that Dr.
Brawley had
brought up, and I think maybe I can
rephrase what
he said.
There is aggressive marketing in areas
where it shouldn't be marketed, and I
will give you
an example.
I can't give you proof, but I
can give you
examples.
Patients with metastatic
hormone-sensitive prostate cancer, if you
look at
267
the absolute indication, there is no
indication in
that setting. Yet, under the umbrella of bone
disease, the drug is being marketed to
the prostate
cancer patients.
If I saw correctly what is up
there, it
seems to me there is almost a
relationship to how
long you live, and then osteonecrosis and
side
effects, if you don't live long enough,
you are not
going to get that side effect, because
you just
died.
So, in those patients, their
average
longevity is three years, some of them
live longer.
I think there is a risk in there. There is
multiple trials from Europe that showed
no benefit
to the addition of bisphosphonates albeit
second
generation in that setting, so I would be
very
careful about marketing it indirectly.
Otis, is that about something
similar?
The second issue I think is the
issue of
268
frequency and the need to start these
medications,
and I think it is important--I can't
speak about
myeloma, but in looking at the data for
prostate
cancer, correct me if I am wrong, but the
patients
that the drug was tested in were really
far
advanced prostate cancer patients.
This is not the patient whose
PSA went
from 0.1 to 0.3, and the unfortunate
approval is a
blanket approval, you know, anytime you
develop
androgen-dependent disease, you are going
to go get
the drug, and yet, if I am not mistaken,
again,
correct me if I am wrong, the median PSA
for these
patients that went on it is in the
several
hundreds.
So, not only I think education
needs to be
given about the setting, but actually the
timing of
its use, and not the minute the patient
becomes
androgen independent.
DR. MARTINO: Dr. Perry.
DR. PERRY: I would like to ask Dr. Young
or someone from the company how many
patients get
this product a year?
DR. YOUNG: I am going to have to call on
Dr. Deborah Dunsire again. How many?
Do you want
in the U.S.?
269
DR. PERRY: It doesn't have to be to three
decimal points. I mean are we talking about 5,000,
50,000, 500,000?
DR. DUNSIRE: It's variable by indication.
To be clear, lung cancer patients
generally get it
for a shorter period of time. So, overall, we know
that since 2001, about a million patients
have been
treated.
There are probably several hundred
thousand treated at some point during a
year.
DR. PERRY: In the United States?
DR. DUNSIRE: No, that would be global.
DR. PERRY: How many patients in the
United States get this drug per year?
DR. DUNSIRE: I would have to look to get
you exact figures, but it's in the tens
of
thousands.
DR. PERRY: Tens of thousands, and we have
given out 55,000 booklets. It doesn't seem to me
to be enough.
DR. DUNSIRE: Right, there would be less
than 55,000 patients, however, in a year.
DR. PERRY: My assumption is that you have
reached 25 percent or less of the
patients.
DR. DUNSIRE: We are actively continuing.
DR. PERRY: I understand that, but I am
270
trying to get a handle on the magnitude
of the
problem.
DR. DUNSIRE: Absolutely.
DR. PERRY: It seems to me that there a
lot more patients who get the drug than
get the
booklet.
DR. MARTINO: Dr. Proschan.
DR. PROSCHAN: I think that the reaction
of Novartis is somewhat defensive, and I
think that
hurts.
I am looking at this, the adverse
reactions, and the first sentence is,
Osteonecrosis
of the jaw has been reported in patients
with
cancer receiving treatment regimens
including
bisphosphonates. Now, if you read that just a
little bit differently, I realize there
is no comma
in
there, but you could read that as Osteonecrosis
271
of the jaw has been reported in patients
with
cancer receiving treatment regimens
including
bisphosphonates.
In other words, it has been
reported with
a number of regimens, and this is one of
the
things.
That may very well have been accidental,
but I think it comes off as being
defensive. Many
of these patients were also receiving
chemotherapy,
you know, and I think it would be a lot
better to
take those defensive things out.
DR. MARTINO: Is that wording from the
company or is that wording from the FDA?
DR. PAZDUR: This was negotiated, labeling
changes, that we were in discussion and
agreed
with, with the sponsor, but we will be
more than
willing to renegotiate these if the
committee feels
that this is too weak.
DR. MARTINO: I just wanted to make that
clear.
I mean it is not really entirely their
choice of wording. I mean it's an interaction.
DR. PROSCHAN: Like I said, that first one
may very well have been accidental. I mean even if
272
you changed it to, instead of including
bisphosphonates, if you change it to
"that include
bisphosphonates," that is a minor
change that
doesn't have that potential
misinterpretation.
DR. MARTINO: I think for me the issue is,
you know, as time is going on, there are
more and
more of these cases, recognizing that we
don't know
the denominator. So, perhaps what might have been
an appropriate stance to take, you know,
a year ago
or 18 months ago, may be not quite
appropriate
today, that we know more right now in
terms of the
fact that, yes, this does occur.
The other thing I have to say I
don't have
a real sense of is the severity of
this. I mean I
have seen one speaker this morning imply
that these
tend to be fairly minor issues, and then
I have
seen another speaker with a very
different
experience.
So, as a clinician, I am just
kind of here
struggling trying to figure out, not only
is the
frequency of this problem, but I don't
feel I
really have an understanding of that.
DR. REAMAN: I would echo the same thing
and again I would also criticize we are
being asked
to comment on the materials that have
been provided
273
to patients and the public without having
had the
opportunity to review them.
But I am totally baffled about
this whole
entity, which has been attributed to
bisphosphonates. We have heard people claim that
they have never seen it before in their
lives or
rarely saw it, but yet it is associated
with a
number of well-established risk factors
is what it
says in this.
So, if we know so much about
it, that it
is associated with well-established risk
factors,
it seems to me a great deal of double
talk. As a
physician, I don't understand what this
statement
says.
As I patient, I am certain that I wouldn't
have been able to understand.
DR. MARTINO: Rick, did you have something
you wanted to say?
DR. PAZDUR: Well, by no means I don't
think it is anyone saying that this is a
trivial
274
situation, and with any clinical
expression of a
toxicity, there are various
manifestations of it
that could be progressive in many
patients, but I
want to make sure.
The reason why we are having
this meeting
is to bring attention to it. We, at the FDA, are
somewhat limited in what we could do to
notify the
public.
We change labels, we send out e-mails, we
had advisory committees, and I think is
kind of the
apex of what we could do with the
toxicity, to
spend time in an open public forum to
bring this to
people's attention here.
I don't think it is well
characterized,
and I think the surrounding areas that
are
associated with it are areas that are
characteristics of patients that have it,
whether
they are causal effects, whether they are
casual
associations, I think that is to be
further
delineated and to be further examined
with more
time.
DR. BERENSON: May I comment briefly on
this? Every patient who is seen in our
practice is
275
informed of the renal risks, the
osteonecrosis of
the jaw risk, as well as the flu-like
symptoms in
detail, and every patient is evaluated by a
dentist
now before they actually begin therapy.
In addition, those patients
with possible
jaw problems are referred to an expert at
UCLA for
further evaluation. The spectrum of patients that
I am seeing are amongst everybody who
gets treated
with bisphosphonate for myeloma, so I am
not seeing
necessarily the extreme cases, I have
seen just
six, but I can only comment on my own
experience,
but
we are very aggressive about making sure these
patients are informed about this
complication.
DR. PAZDUR: Unfortunately, perhaps many
aren't, as was pointed out by the oral
surgeon from
Kaiser, medical oncologists don't get
into people's
mouth many times. That isn't a focus of some of
their examinations, and especially in an
unrecognized problem, they may not be
paying
attention to this.
Many patients are started on aggressive
chemotherapy regimens without a visit to
the
276
dentist or without a really thorough
examination.
Here again, I think this points out not
only to a
problem with a drug, but also a problem
with our
practice of medicine in oncology, that we
need to
pay more attention to, so there is
various factors
that go into this.
DR. MARTINO: As a clinician, I am not
sure that I have even a clear
understanding of how
I would recognize this. In other words, what would
the patient say to me other than it hurts
here,
Doctor, and they would be pointing to
their jaw.
I mean I don't have an understanding
that
if I sent them to a dentist, the dentist
will do
anything more than I would do, which is
to look in
the mouth and decide if they need a tooth
pulled or
some gross basic thing like that.
What I am most at loss of is an
understanding of what is the actual
behavior of
this disease, and if the company has the
ability to
sort of characterize it, that would be
great.
DR. PAZDUR: You have Dr. Ruggiero here, I
believe, and perhaps he would like to
address this.
DR. YOUNG: I will invite Dr. Ruggiero. I
just want to say I think this is a
critical
condition, and based on the kinds of
information
277
that we have now, which is spontaneous
reports, it
is very hard to sort out these things.
I mean we have a variety of
symptoms and
signs that are reported. You know, we may have a
mixed group of cases at this point, so I
think this
is why we really critically want to put
together a
definition, a severity system, a grading
system, so
that we can prospectively look at this
going
forward and get a better idea of the
natural
history.
DR. PERRY: Yes, I think that is where the
FDA could really do something instructive
is to get
together a group of experts and come up
with a
scoring system, so that if what we have
seen are
Grade 4's on the usual CTC system, we
would have a
better idea of what kind of elephant we
are dealing
with.
DR. MARTINO: Dr. Brawley, you are next.
DR. BRAWLEY: Dr. Hussain was much more
278
eloquent in describing the question I
have. I
remember when Novartis brought this
before the ODAC
before, and we suggested that it might be
approved,
and I don't regret voting for it being
approved,
because I think there is some benefit to
the drug,
but I recall that of the skeletal-related
events
that they talked about, and the decrease
in the
skeletal-related events, they increased
the number
of events found and increased the number
of events,
reduced in the Zometa arm by doing
screening of the
spine with x-rays.
So, many of the
skeletal-related events
that were prevented with Zometa were
asymptomatic
fractures that were here nor there to the
patient,
but they were prevented nonetheless.
So, when I see that and I heard
about the
advantages of Zometa, I worry about is
the
promotion of the drug as accurate as I
would like.
DR. MARTINO: Dr. Reaman.
DR. REAMAN: Just a question. Are there
any kind of screening studies that could
be done?
I mean when I go to the dentist and say
something
279
hurts, the first thing that is done is
x-rays. I
mean is there a recommendation for doing
some sort
of radiographic studies based on duration
of
exposure?
DR. YOUNG: I am going to ask Dr.
Landesberg. I want an oral surgeon to speak about
this.
DR. LANDESBERG: Regina Landesberg from
Columbia University. I believe that as far as a
screening exam, we have documented what
we would
recommend for that, and it really just
includes
something that should be done by every
dental oral
surgical professional, a complete oral
exam,
examining the head and neck structure,
but it
really requires that you are diligent.
We believe that there will be
some
predictive indices and we may be able to
see
changes on radiographs, but that has not
been
established at this point. I do believe that we
can find some predictive indices that
will indicate
who is going to be at risk for this
disease.
DR. REAMAN: I think it's great that
280
dentists are made aware of this, but are
oncologists who are prescribing this made
aware of
this, and are they being told that this
is
something that they have to do for
patients for
whom they are prescribing this drug.
DR. MARTINO: Actually, that may really be
a very worthwhile thing to do. I mean I will tell
you I have never had the habit of sending
my
patients to a dentist prior to this, and
I don't
know that that would solve the problem,
to be
honest with you. I am not sure right now that I
have that feeling, but it is not an
unreasonable
thing to do.
DR. PERRY: I was wondering, you know, I
was a little troubled when I first looked
at this
by the fact that the same doctor had
reported so
many of these cases, I am just wondering
whether
this is something that is very easy to
see and
confirm, and whether anyone else did
confirm those.
DR. MARTINO: I think we have got that
doctor here, and I must admit I had that
same
reaction as to was this somehow a
selected are we
281
looking for.
DR. RUGGIERO: Well, there are a bunch of
questions that I have to address here.
First, it was, when we first
started
seeing these problems, very interesting
to me that
we were the only center that was seeing
such a
number of cases, we were really were. At the
beginning, we were seeing 10, 20 cases
where people
weren't seeing this at all.
As of yesterday, I logged the
105th
patient in our local database in my
practice alone,
and I don't know why we are seeing so
much.
Clearly now, because of all the
publicity, I am
seeing more and more patients, but a lot
of them
are local people.
The spectrum of disease, as you
have
mentioned before, there is truly a
spectrum from
small, little tiny areas of exposed bone
that are
very easy to diagnose. This is not something that
is rocket science to diagnose. It's simple, it's
easy.
You look in the mouth, you see exposed bone,
you have a diagnosis.
So, yes, I don't expect the
oncologist to
be looking in the mouth, but if an
awareness is
sort of made to the patient that this is
a possible
282
problem, then, the diagnosis can be easily
made.
There is a spectrum, and we have seen
that here
today.
Dr. Levine showed cases of massive exposure
of bone.
I have many cases like that. Likewise, I
have many cases with small, little areas
of exposed
bone that remain quiescent over a very
long period
of time and respond very well to
treatment.
I have a lot of patients who
have not
responded to treatment, and have done
very poorly
and lost their job over this
complication, and it
is very frustrating because we don't have
any
clinical indices right now to predict who
is going
to be the person who loses their job, who
is going
to be the person that is going to
continue to do
well on rinses alone.
I think one of the things that
has to come
out of this meeting and meetings like
this, is to
educate the patients, educate the
oncologists, and
more importantly, educate the general
dentists,
283
because I think the dentists are probably
the ones
that are kind of caught in the middle
here. They
are looking at things, and they don't
really know
what they are looking at.
Oftentimes, it winds up in the
oral
surgeon's office and they are now one of
the
professional groups that is probably more
aware of
this than any other group, probably oral
pathologists, as well, since they are reading
all
these specimens.
The oncologists are a distant
third, and I
think that is getting better, but I think
the main
focus at this point is to educate the
oncologists,
and
that is going to be as well as myself, and a
few of my colleagues, to educate the ADA,
and we
are doing that in the process of getting
some of
this data off to them.
But, if you have any more
questions?
DR. MARTINO: Doctor, when you see these
patients, what do you do as a way of
managing the
problem, how do you, quote, unquote
"treat"?
DR. RUGGIERO: It depends upon the
284
symptoms that they have when they
present. If they
present with exposed bone, but they are
asymptomatic, they have no pain, they
have no
evidence of infection, I do relatively
nothing.
The main goal here, in my mind,
is to
maintain the highest quality of life
possible,
because this problem, if left unchecked,
or if it
progresses, can be in many patients' own
testimony
to me, is worse than any other
chemotherapy they
have ever gotten, because it can be very
painful.
So, if they present and they
have exposed
bone, but they are asymptomatic, we leave
it alone.
The worst thing to do in my mind, and I
have been
through this loop because when we first
started
seeing these patients, we thought this
was just
exposed necrotic bone, we went after it
surgically.
I took jaws off, I took sections of jaws
off. They
don't heal, and we have made it worse.
So, we have to learn, as a
profession, to
put the scalpel in the holster most of
the time,
and just follow these patients, and when
they are
symptomatic with pain infection, hit them
hard with
285
antibiotics.
Now, these are recommendations
that have
developed over the course of time based
on my
experience and a few other oral surgeons
across the
country, and we have come to somewhat of
a
consensus.
Is it based on a lot of good
data? The
answer is no, it's my own personal
preference, and
we have had some success with it. It has to be
looked at in a more structured way.
There have to be some
prospective studies
looking at why this happens, how to
prevent it, how
to identify patients who are at risk of
developing
this, and we just don't know that right
now.
DR. MARTINO: Yes.
DR. AVIGAN: I was just going to emphasize
the importance to distinguish between
case
identification criteria where the
clinician would
be prepared to identify the case and then
appropriately manage it, and prevention
and risk
mitigation, which is really a different
arena,
where we clearly from what we have heard
today,
286
need more information to determine the relationship
between duration of treatment, cycled
therapies,
susceptibility factors, is there a
threshold effect
of what the total dose is, and that would
then
inform benefit-risk for those patients
who might
have a longer course disease.
So, you have to think about the
natural
course of the disease that they have, on
one side
of the scale, and then the other side is
the
natural course of the treatment and its
effect on
the hazard and risk over time, which
needs to be
studied.
DR. MARTINO: Thank you.
Dr. Pazdur, do you have any
other needs
from this committee today? Are there questions you
have that we have not answered for you?
DR. PAZDUR: I think some of the questions
that we have laid out here perhaps don't
have
answers at this time. I think we have
evolve that
data.
In my own mind, listening to what has been
said, I think there are several major
areas that
Novartis, FDA, the investigator community
have to
287
work on, number one, duration, and I
think that is
an important issue and how optimally to
use this
drug.
The half-life of this drug in
bone is
very, very, very long. Do people need the same
dosing schedule over a long period of
time?
Greater awareness by the community that
treats
this, not only oncologists, oncology
nursing
personnel, oral surgeons and dentists.
Is there a preferential
bisphosphonate,
Aredia versus Zometa? There some very interesting
data that was presented by the group
here. We have
to remember that the basis for approval
in multiple
myeloma was on the basis of a
non-inferiority for
Zometa.
So, is there a big advantage is
we have a
toxicity issue? Here again, we don't know this.
This is data that is hypothesis generating
that we
heard, but these are I think major
questions that
need to be answered and hopefully they
can be
answered.
Here again, our reason for
bringing this
288
to the committee, we really wanted to
highlight the
safety issue. It's an important issue. This is
one of the few opportunities that we get
to have a
public face to the FDA, and I think that
this is
important to illustrate, not only
efficacy, but
important safety issue.
So, I thank you and I don't
have any
questions at this time.
DR. MARTINO: Thank you, and this meeting
is adjourned.
[Whereupon, at 1:27 p.m., the
meeting
adjourned.]
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