FOOD AND DRUG
ADMINISTRATION
+ + + + +
CENTER FOR DRUG EVALUATION
AND RESEARCH
+ + + + +
ARTHRITIS ADVISORY
COMMITTEE
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TUESDAY,
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The
above-entitled meeting was convened in the Kennedy Grand Ballroom of the
Holiday Inn Silver Spring, 8777 Georgia Avenue, Silver Spring, Maryland, at
9:00 a.m., Dr. Steven B. Abramson, Acting Chair, presiding.
PRESENT:
STEVEN B. ABRAMSON, M.C. Acting Chair
KATHLEEN REEDY, RDH, M.S. Executive Secretary
JENNIFER ANDERSON, Ph.D. Member
SUSAN M. MANZI, M.D. Member
H. JAMES WILLIAMS, JR., M.D. Member
WENDY W. McBRAIR, R.N., M.C. C.H.E.S. Consumer
Representative
ARTHRITIS ADVISORY COMMITTEE FDA CONSULTANTS:
STEVEN
B. ABRAMSON, M.D.
JANET D. ELASHOFF,
Ph.D.
ALLAN GIBOFSKY, M.D., J.D.
NORMAN
T. ILOWITE, M.D.
ROBERT
W. MAKUCH, Ph.D.
FDA CONSULTANTS FROM OTHER ADVISORY COMMITTEES:
RUTH
S. DAY, Ph.D.
DOUGLAS
W. BLAYNEY, M.D.
JAMES
E. KROOK, M.D.
ELAINE
S. JAFFE, M.D.
I-N-D-E-X
Page
Call to Order and Introductions................. 4
Meeting Statement, Kathleen Reedy............... 6
Introduction to the Topic and Background:....... 9
Jeffrey
N. Siegel, M.D., FDA
Li
Liang, M.D., FDA
Tim
Cote, M.D., FDA
Ellis
Unger, M.D., FDA
Abbott Laboratories: James Lefkowith, MD....... 72
Steven Fischkoff, MD
Robert Tarone, PhD
Amgen Incorporated: Daniel Burge, M.D........ 115
Alan Silman, M.D.
Centocor Incorporated: Jerome A. Boscia, M.D. 151
Thomas F. Schaible,
Ph.D.
Lunch
Open Public Hearing........................... 195
Introduction to Questions: ................... 215
Jeffrey
N. Siegel, M.D., FDA
Discussion and Questions
Adjourn....................................... 332
P-R-O-C-E-E-D-I-N-G-S
(
CHAIRMAN
ABRAMSON: Good morning. I would like to call this meeting of the
Arthritis Advisory Committee to order.
This meeting is a safety update on the TNF alpha blocking agents. I am Dr. Abramson, NYU and the Hospital for
Joint Diseases, and I would like to begin the meeting by having the committee
introduce themselves, and begin with Dr. Jaffe.
DR.
JAFFE: I am Dr. Elaine Jaffe from the
National Cancer Institute, NIH.
DR.
KROOK: I'm Jim Krook from a community
oncology program in
DR.
BLAYNEY: I'm Doug Blayney. I'm a medical oncologist from Wilshire
Oncology Medical Group in
DR.
DAY: I'm Ruth Day,
DR.
ELASHOFF: Janet Elashoff, biostatistics,
UCLA and Cedars Sinai.
DR.
MAKUCH: I'm Robert Makuch, head of
biostatistics at
DR.
ANDERSON: Jennifer Anderson. I'm a statistician from
MS.
McBRAIR: Wendy McBrair, Director of
Arthritis Services, Virtua Health in
DR.
WILLIAMS: James Williams,
rheumatologist,
SECRETARY
REEDY: Kathleen Reedy, Food and Drug
Administration.
DR.
ILOWITE: Norm Ilowite, pediatric
rheumatologist from Albert Einstein College of Medicine.
DR.
MANZI: Susan Manzi. I'm a rheumatologist and epidemiologist at
the
DR.
GIBOFSKY: Allan Gibofsky, a
rheumatologist at the Hospital for Special Surgery and
DR.
LIANG: Li-Ching Liang, a medical
reviewer at the FDA.
DR.
SIEGEL: Jeffrey Siegel, Acting Branch
Chief, Immunology and Infectious Diseases Branch at the FDA.
DR.
WEISS: Karen Weiss, Food and Drug
Administration.
DR.
WOODCOCK: Janet Woodcock. I'm head of Center for Drugs at the FDA.
CHAIRMAN
ABRAMSON: Thank you. I would now like to introduce Ms. Kathleen
Reedy to read the meeting statement.
SECRETARY
REEDY: This meeting statement is for the
Arthritis Drugs Advisory Committee on
The
following announcement addresses the issue of conflict of interest with regard
to this meeting, and is made a part of the record to preclude even the
appearance of such at this meeting.
Based
on the submitted agenda for the meeting 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 at this meeting, with the following
exceptions.
In
accordance with 18 United States Code 208(b)(3) and 505(m)(4), waivers have
been granted for the following participants:
Dr.
Douglas Blayney for ownership of stock in two of the firms that make TNF alpha
inhibitor; each stock is valued between $25,000 and $50,000.
Dr.
Allan Gibofsky for ownership of stock in two firms that make TNF alpha
inhibitors; one stock is valued between 5 and 25, the other between 25 and
50,000; for consulting for three firms that could be affected by the
committee's discussion for which he receives less than $10,000 per firm per
year, and for lecturing for three firms that could be affected by the
committee's discussions. He receives
less than $10,000 per firm per year. Dr.
Gibofsky consulting and lecturing is general in nature and is not specific to
the products under discussion.
A
copy of the waiver statements may be obtained by submitting a written request
to the agency's Freedom of Information Office, Room 12-A-30 at the
Dr.
John Cush has been excluded from participating in today's discussions due to
his current involvement in studies and past consulting on TNF alpha inhibitors.
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.
CHAIRMAN
ABRAMSON: Thank you. We will begin the meeting with presentations
from the agency, from CBER. Just a
couple of words on the ground rules. We
would like each of the presenters to try and keep to their time frame, because
we have an awful lot of important information to cover.
The
committee members, at the end of each presentation, will be able to ask a few
questions for clarity, but we would like to leave any general discussion about
the area covered to later in the afternoon.
But if there are specifics that people want more information on from the
presentation, that would be okay.
So
I'd like to call on Dr. Siegel, Jeffrey Siegel, to present -- to introduce the
topic and the background.
DR.
SIEGEL: Thank you very much. Ladies and gentlemen, good morning. In our presentations this morning, the FDA
will present a safety and efficacy update on the three approved TNF blocking
agents.
The
first TNF blocking agent that was approved was etanercept which received
approval in 1998. Shortly thereafter,
infliximab, or REMICADE, was approved in combination with methotrexate for treatment
of rheumatoid arthritis, and just a few months ago in December of 2002
adalimumab, or HUMIRA, was also approved for treatment of patients with
rheumatoid arthritis.
Each
of these three agents has demonstrated high ACR, or
Some
of these studies have been carried out as monotherapy, but many of the studies
have also been carried out with combination with background DMARDs or as add-on
to methotrexate.
While
these products that have shown efficacy, each has also been associated with
uncommon but serious adverse events.
Etanercept is approved for use as monotherapy or in combination with
methotrexate for moderately to severely active rheumatoid arthritis.
I
want to point out that, when I say monotherapy, this does not necessarily mean
that the product is the only product used for rheumatoid arthritis. Generally speaking, the studies of
monotherapy for this agent and others were carried out with patients receiving
background low dose corticosteroids and nonsteroidal agents.
Etanercept
is approved for improving signs and symptoms of rheumatoid arthritis and for
inhibiting the progression of structural damage. Additional indications which etanercept has
received include polyarticular-course juvenile rheumatoid arthritis and
psoriatic arthritis.
Infliximab
is approved for use in combination with methotrexate for moderately to severely
active rheumatoid arthritis. The claims
are that Infliximab has obtained including improving signs and symptoms of
rheumatoid arthritis, inhibiting the progression of structural damage and improvement
in physical function, based on a two-year study involving the Health Assessment
Questionnaire or HAQ.
Infliximab
is also approved for treatment of Crohn's Disease, and in this way it differs
from Etanercept. It is indicated for
treatment of patients with Crohn's Disease with active disease. In the studies, that was defined as a CDAI
score exceeding 220. That is the Crohn's
Disease activity index. And Infliximab
is also approved for treatment of patients with fistulizing Crohn's disease.
Adalimumab
or HUMIRA, as I mentioned, was approved in December of 2002. This is a monoclonal antibody to
TNF-alpha. The sequence is entirely
human derived. However, studies indicate
that HUMIRA does have immunogenicity, as I will touch on a bit more later.
The
pivotal trials of Adalimumab assessed its safety and efficacy as monotherapy,
in combination with methotrexate, and as add-on treatment to standard of care
in a general rheumatology practice situation.
It was approved last December.
This
slide shows the results of the three large pivotal trials of Adalimumab. The top set of rows shows the results --
Well, one of the studies was as monotherapy.
The other was methotrexate combination, and the third study was a study
of add-on to standard of care.
As you can see, while it is difficult and
problematic to compare across studies, the highest point estimates were seen in
the study of methotrexate combination where 63 percent of patients had an ACR20
response, compared to 30 percent with placebo.
Adalimumab
was also shown to be efficacious when used as monotherapy and as add-on to
standard of care, and here the ACR20 response rates were 46 percent and 53
percent. The ACR50 response rates for
methotrexate combination were 39 percent and 22 percent and 29 percent in the
monotherapy and add-on to standard of care study. In addition, ACR70 rates higher than placebo
were shown.
Adalimumab
was approved for use as monotherapy or in combination with methotrexate or
other DMARDs for treatment of rheumatoid arthritis. It is approved for improving signs and
symptoms of rheumatoid arthritis and for inhibiting the progression of
structural damage.
Let
me make a couple of points about dosing and administration of Adalimumab. The recommended dose is 40 mg every other
week subcutaneously. This dose is the
optimal dose for methotrexate combination.
However, with monotherapy, 40 mg every other week is efficacious, but
higher response rates were seen with 40 mg every week. This was not the case for methotrexate combination,
where higher doses were not more efficacious.
Monotherapy
has been associated with higher rates of antibody formation than use with a
combination methotrexate. We observed 40
percent antibody formation in methotrexate combination and 12 percent when
monotherapy was studied, and immunogenicity is associated with lower ACR
response rates.
I
am going to turn now to safety update, and this will be the subject of the rest
of my presentation and the rest of the FDA's presentations, and this is intended
as a follow-up to the comprehensive August 2001 presentation in front of the
Arthritis Advisory Committee.
We
plan to present an in depth discussion of new data on previously recognized
serious adverse events, as well as some newly recognized serious adverse
events. We will cover the TB experience
with adalimumab, an evaluation of lymphoma, malignancies with all TNF blocking
agents, some data on liver injury with infliximab and etanercept, and some data
on randomized controlled trials of TNF blocking agents in congestive heart
failure.
The
data that you will see is based on a variety of different sources, and this
makes the analysis fairly complicated.
One source is controlled clinical trials, but a lot of the data is from
other sources, including open-label extension studies. And I want to mention here that each of the
companies has agreed to a post-marketing commitment to study 100 to 2000
subjects for five years to assess malignancies and serious infections.
Other
data is derived from post-marketing registries and also from spontaneous
post-marketing reports.
Several
serious adverse events have been observed with each of three approved TNF
blocking agents. This includes serious
infections, including tuberculosis, opportunistic infections including
histoplasmosis, listeriosis, coccidioidomycosis, and pneumocystis carinii
pneumonia, as well as non-opportunistic infections.
All
three agents have also been associated with demyelinating events and with
autoantibodies and the development of new autoimmune disease, in particular
very uncommon cases of lupus-like syndrome.
For
etanercept and infliximab,the safety concerns are most generally based on
post-marketing reports. However, some of
the concerns have emerged in controlled trials in other diseases than
rheumatoid arthritis. However, for
adalimumab, a much larger safety database was obtained and available at the
time of approval, and you will hear more about this later.
So
the same serious adverse events were observed pre-marketing. So we have a much better idea about their
incidence for this product. Many of the
serious adverse events are consistent with known mechanism of action of these
agents. That is an inhibition of an
important arm of host defense, for example, infections and possibly lymphoma.
Other
serious adverse events are unanticipated
-- for example, deleterious effects on patients with congestive heart failure,
and also demyelination.
The
agency has communicated the risks as they have emerged in a variety of ways. They are stated in the package insert under
the Precautions section, in the Warning section and, where appropriate, as a
boxed warning.
The
agency has asked the companies to issue "Dear Healthcare Provider"
letters. The agency has published peer
reviewed scientific publications communicating these safety concerns. We have presentations to the Advisory
Committee, including the most recent one in August of 2001, as well as
presentations at medical meetings, including several presentations at the
Let
me make a couple of points about the package inserts. It has been noted by a number of people that
the warning is not identical for each product for the safety concerns that we
have talked about. What the FDA has done
in deciding on the appropriate language is to look at the data available and,
where the data are similar, especially where there is a biologic rationale,
class labeling may be warranted. But
where the data differ, different language may be appropriate for different
agents.
For
an example, I would like to talk about tuberculosis, which differs in the
infliximab and the etanercept label. For
infliximab, tuberculosis was seen in the clinical trials. Cases of tuberculosis, some fatal and some with
-- many with unusual presentations, were observed in post-marketing reports.
The
reporting rate, based on the post-marketing data, was estimated to be
severalfold higher than the incidence in the
Many
of these cases of tuberculosis occurred in patients who were not otherwise
considered at risk for tuberculosis.
Based
on these data, a boxed warning was put into the REMICADE label, and screening
and prophylaxis is recommended for all patients.
With
etanercept, uncommon cases of tuberculosis were seen in the post-marketing
experience. The estimate of report --
The reporting rate was similar to the
No
cases of tuberculosis were seen in the rheumatoid arthritis trials of
etanercept in the
Now
why would adverse events differ between the different TNF blocking agents? There are a number of potential
explanations. For one, the products have
somewhat different mechanisms of action.
Etanercept
is a soluble receptor that neutralizes TNF alpha and also lymphotoxin. Monoclonal antibodies work slightly
differently. They neutralize TNF but do
not neutralize lymphotoxin.
The
different products have different affinities for their ligands and different
avidities of binding. They have
different ability to lyse TNF bearing monocytes in vitro and possibly in vivo
as well, and the products differ in their immunogenicity.
These
differences may contribute to unique efficacy and safety properties of the
different agents.
So
our agenda today is to update the committee on the known adverse events and on
newly documented adverse events with the TNF blocking agents. We will be focusing on tuberculosis,
malignancies and lymphomas, liver enzyme elevations and hepatic adverse events,
and congestive heart failure. We will
also discuss some of the challenges in interpreting open label and
post-marketing safety data.
These
are the presentations. The next one will
be given by Dr. Liang. He will discuss
lymphoma and tuberculosis.
CHAIRMAN
ABRAMSON: Are there any questions for
Dr. Siegel? Thank you, Jeff.
DR.
LIANG: Good morning, ladies and
gentlemen. Excuse me.
DR.
WEISS: Sorry. We have these fancy transition slides that we
want to get rid of.
DR.
LIANG: Good morning. Sorry for that delay. The outline of my talk will be to update the
committee on safety data from clinical trials and post-marketing reports, as
Dr. Siegel had mentioned, and also specifically to focus on adalimumab and
tuberculosis, followed by the experience of all the TNF blockers with
malignancies and lymphoma.
Just
as a background slide, in the adalimumab safety database, at the end of the
Phase 2 meeting with the agency, FDA had recommended to Abbott to develop a
larger safety database because of the serious adverse events that were seen in
post-marketing studies with infliximab and etanercept.
to
that end, Abbott studied for safety a total of 2070 patients in controlled
trials with a mean exposure of seven months, and over 2400 patients in open-label
studies with a mean exposure of 24 months.
It
is important to keep in mind, however, that the interpretation of open label
data is difficult due to a lack of concurrent control group, though this larger
experience and the duration of such trials are beneficial.
In
early clinical experience with adalimumab, there were eight cases seen
initially in the first 542 patients treat with adalimumab. After discussions with FDA, screening and
prophylaxis measures were begun.
In
As
a result, there was a reduction but not complete elimination of tuberculosis
following these screening and prophylaxis measures. Five cases were subsequently diagnosed in the
next 1900 patients treated with adalimumab.
This
reduction in TB may have also been contributed due to lower doses used in
further studies and enrolling fewer patients from highly endemic areas.
The
characteristics of the TB cases include the following: Most reported TB cases from European studies
and European sites and were more frequent in patients receiving higher than the
licensed dose of 40 milligrams every other week. Most cases were extrapulmonary, and most
occurred in the first eight months of therapy in controlled trials.
This
may reflect a reactivation of latent infection.
As a result, a boxed warning was incorporated into the package insert..
Because
of the immunomodulatory properties of TNF blockers, there is obvious concern
about malignancies with long term treatment of these products. The assessment of malignancies in relation to
these products, however, is difficult, because it is hard to maintain a
comparator control arm in long term studies.
On
approach would be to compare observed malignancy rates to the expected rate in
the general population; for example, using the SEER Database which adjusts for
age, gender, race, and geography to calculate standardized incidence ratio or
SIR.
With
regard to malignancies in the rheumatoid arthritis population, the
interpretation of data is even more complicated due to several factors. First off, the lymphoma incidence is reported
to be several-fold higher among RA patients, especially those with higher
levels of disease activity and inflammation.
The
other issue with malignancies in rheumatoid arthritis patients is that most
patients that are enrolled in clinical trials already have highly active
disease, and most receive concomitant DMARDs with immunosuppressive properties.
This
first data table that I will show you represents the malignancies that have
been seen with adalimumab in controlled portions of controlled trials.
This
distinction is very important, because the controlled portions excludes the
patient data that were obtained on the follow-up period, and it is also
important because it also gives us a common denominator, if you will, in which
to compare other drugs for their treatment times.
In
adalimumab treated patients, there were a total of eight malignancies observed
out of their controlled trial denominator, if you will, of 1380 patients that
were treated for a mean duration of 0.6 years.
In the placebo group there were zero malignancies that were seen in
controlled clinical trials.
The
lymphomas that were observed with adalimumab in controlled portions of
controlled trials numbered two. Again,
the number of patients was the same.
This
table shows the observed versus expected cancer rates for the entire adalimumab
clinical development program through August of 2002. A total of 46 malignancies were diagnosed,
and the subcategories of lymphomas is highlighted, because the SIRs,
Standardized Incidence Ratios, are above 5, and with 95 percent confidence
intervals that do not overlap 1.
The
10 lymphoma cases by type according to REAL classification are listed
below. As you see, 5 out of 10 or half
of the lymphoma cases that were diagnosed are of the diffuse large B-cell
lymphoma type, and the other pathological categories are listed below.
We
are going to move on to the experience of etanercept with relation to the
malignancies and lymphomas seen in their trials. In controlled portions of clinical trials
with etanercept, there were a total of 12 malignancies seen in the etanercept
treated patients versus 5 in the placebo treated group.
I
have here that one lymphoma was observed in the etanercept treated group. Of these 12 and 5 malignancies, they are
represented in this next table and, as you see, we have quite a wide variety of
malignancies that were diagnosed in the controlled portion of etanercept
trials.
The
next slide represents the number of malignancies that -- number of lymphomas
that were seen in the entire etanercept clinical trial database. With over 3300
patients representing over 7300 patient years of data with a mean exposure of
2.2 years, six lymphoma cases were reported in all clinical trials, with an
additional 3 cases reported after the follow-up period. The calculated SIR with these data is 2.31,
with 2.6 cases expected based on the SEER database.
The
next few slides pertain to the experience of infliximab. This slide represents all the malignancies in
the controlled portions of controlled trials seen with infliximab. It also includes the ASPIRE data, which is
currently blinded data. I just want to
mention that, for the ASPIRE data, any malignancy was counted as if it was
related to the infliximab arm, giving sort of a worst case scenario, if you
will. But it is important to keep in
mind that these data are still blinded.
In
infliximab treated subjects, there were a total of 22 malignancies for all
controlled portions of controlled trials.
In the placebo treated subjects, there was one malignancy, giving us a
total of 23 malignancies.
The
next slide is a listing of all the malignancies seen in the controlled portions
of controlled trials, including the ASPIRE data. As you see, there is also a wide
distribution. However, there are three
lymphomas that were diagnosed, and the majority of the cases were based on
non-melanoma skin cancer.
This
next slide looks at the number of lymphomas seen in controlled portions of
controlled trials for infliximab. For
infliximab treated subjects, there was a total of 3 lymphomas diagnosed, and
this is in comparison to zero lymphomas seen in placebo treated subjects. These patients were followed for a mean
duration of treatment of approximately a year through all studies.
This
slide looks at all of the malignancies seen with infliximab in all clinical
trial experience. You see here, for the
observed number of cases of malignancies this number is 27. For placebo treated patients, the number is
four.
The
number of lymphomas in all the clinical trial experience is displayed
here. For all studies, there were a
total of six lymphomas seen in all the clinical trial experience, and zero in
placebo treated subjects.
So
our conclusions are that lymphomas have been observed with all three TNF
blockers, although these are small numbers with relative short exposure in
controlled portions of clinical trials.
For the entire database, the calculated SIRs are between two and seven
compared to the SEER database. However,
a more appropriate comparison would be to the RA population, but accurate
incidence rates are not available.
One
to three cases of lymphomas have been diagnosed in treated groups for each TNF
product, versus zero in the control groups.
That gives us a total of the data that I showed of six lymphomas versus
zero across all controlled studies.
The
biological plausibility of lymphomas associated with these immunomodulatory
agents, along with the data presented, raise concern about the causality. Thank you.
CHAIRMAN
ABRAMSON: Excuse me. Dr. Liang, I had a question. Maybe others do as well.
In
the comment that a more appropriate comparison would be to the RA population,
unless I misunderstood, were not the clinical trials -- obviously, the placebo
arms were RA patients, and the rates were still different between the placebo
group and the treatment group. Is that
true?
DR.
LIANG: That is correct. We put that in, because with the subset of RA
populations, it is not -- I don't think it is completely agreed upon as to the
high -- what the high risk is of malignancies and lymphomas with the RA
patients, in particular.
DR.
SIEGEL: Could I comment on that
also? For the controlled portions of the
controlled trials, the appropriate control is there, as you point out, with the
RA population using the placebo groups.
The problem is with the long term extension studies which makes up the
bulk of our experience.
There,
to calculate a standardized incidence ratio, you need to use a comparison
group, and we don't have accurate numbers on the incidence in the RA population
for that part of the data.
DR.
WILLIAMS: Can I just clarify something
you asked, Steve. That is: When you are looking at etanercept data, is
it only the RA data you are looking at or did you include data from psoriatic
arthritis?
DR.
LIANG: That data was from just RA.
DR.
MANZI: I was wondering if you had any
data on spontaneous regression. I'm
thinking about some of our methotrexate experience with stopping the drug. In any of these trials, do you know if there
has been spontaneous regression with discontinuation of therapy?
DR.
WEISS: I'll just briefly comment. There is a population that was included in
your handout published -- Two of the authors are sitting right behind me, and I
will ask them if they want to make a comment.
But they published on a series of approximately 26 cases. Actually Dr. Elaine Jaffe was also involved
in reviewing, I believe, some of the slides for those cases.
I
believe in one or two of those cases there was spontaneous regression once the
TNF therapy was removed.
DR.
BLAYNEY: In the studies that you
described in those disease conditions, once the control group finished the
controlled treatment, was cross-over to active therapy allowed?
DR.
LIANG: It was allowed. However, it was not included in the
controlled portions of controlled trial data.
DR.
BLAYNEY: But those people, if they did
cross over, might pollute the data or add to the safety data, if they developed
lymphomas. They would be counted as an
adverse event associated with the treatment rather than the placebo in your
broad safety data, it sounds like.
DR.
LIANG: Well, I think that's the issue
here with regard to how to actually count patients that crossed over from
placebo to treatment arm. Jeff, do you
want to comment on that?
DR.
SIEGEL: For the analyses that involved
just the controlled portions of the controlled trials, of course, that wouldn't
be a concern. But for looking at the
drug versus placebo for the total safety databases, that would be a concern.
Generally,
patients who crossed over were not ascribed to the placebo group for that. Their duration of follow-up ended at the
point of cross-over. But you are
absolutely right, that there was longer follow-up, therefore, for the drug
treated patients than the patients in the placebo arm.
CHAIRMAN
ABRAMSON: Dr. Krook, do you --
DR.
KROOK: It was the same question.
CHAIRMAN
ABRAMSON: Okay. Dr. Gibofsky.
DR.
GIBOFSKY: Seeing the medians and the
means for the cases that you have arrayed, but have we had a chance to look at
whether or not there is any segregation as a function either of dosage
cumulatively or as a function of onset since time of initiation of therapy?
DR.
LIANG: No. That's a good question, but we have not
looked at the doses.
DR.
SIEGEL: We have done some analyses of
the occurrence with -- based on the duration of treatment, in particular with
adalimumab, and the data did not indicate an increasing incidence with longer
durations of exposure.
DR.
GIBOFSKY: And what about for etanercept?
DR.
SIEGEL: I can't recall those data
exactly. Perhaps the sponsors later on
would have that data.
CHAIRMAN
ABRAMSON: Okay, thank you. Thank you, Dr. Liang. The next speaker is Dr. Cote, lymphoma and
hepatic toxicity.
DR.
COTE: Good morning. Happy Mardi Gras for those of you who are
celebrating it later. My name is Tim
Cote. I am in CBER.
Today
I am going to be talking about lymphomas and liver failure. Most of my time will be spent on lymphomas and
with TNF blockers, but this is with a different kind of data, and I want to
introduce the data type. It is
post-marketing surveillance, also known as the MedWatch program, to somebody
who may have submitted reports through it.
This
is a system, sort of an open door through which clinicians and others can
report adverse events associated with drugs. We call this an epidemiology
passive surveillance. We don't actively
solicit the reports, but we receive them as clinicians voluntarily come forward
with them to report important events sort of as they function as good citizens
in the clinical community.
The
greatest benefit of the system is as a means of signal detection. There are some characteristics of those
reports that need to be borne in mind before I present the data.
First
of all, it is voluntary. There's no laws
like we have for other reporting of diseases in public health for clinicians,
but it is mandatory that the companies report into the FDA whatever reports
clinicians have sent in to the companies.
It
is often incomplete, and it is incomplete in two ways. First of all, there may be an unreported
number of cases. We can't say with any
measure of certainty whether we have 2 percent, 10 percent, 50 percent or 80
percent of the cases which actually occur out in the real world through the
system.
It
is also incomplete in that the narratives, the descriptions, the clinical
descriptions are just volitional reports on the parts of clinicians. So they may lack important information. They may be sketchy.
When
we receive them, they are coded into what we call MedDRA terminology, using a
code book. A clerk will go through and,
whenever they pick up particular terms, they will assign a code number to it,
and it is done with a high degree of sensitivity intentionally so that we may
pick up all of those terms that may be in the report.
Causality
assessments from these are tenuous by design.
We don't have a bar or a requirement of causality in order to receive
the reports and includes them in our database and later reviews what we rest
upon. I'm going to show you some of that
later.
Most
importantly, you can't generate incidence rates from this data, because you
don't know what proportion of the numerator you actually have got.
Turning
now to lymphomas with TNF blockers, there is a rich body of medical literature
associating immunodisregulation and lymphoma, and that is the reason why many
of us are here today, because it is biologically plausible that the TNF
blockers might cause lymphoma. There's
some reasonable reason to expect that that may be the case.
At
this point, at this date in our history, we have hundreds of thousands of
patients on these drugs, and this increases the public health importance of
this committee's consideration.
As
has already been mentioned, we have previously published and included in the
briefing document a series of 26 lymphomas arising from people who were on TNF
blockers, but the causality was explicitly stated in that manuscript as being
unclear and subject to further consideration here.
A
little bit of more understanding on lymphomas and TNF blockers: As was already mentioned, rheumatoid
arthritis and non-Hodgkin's lymphoma are recognized in the medical literature
to be associated, and this does complicate the problem of ascribing or not
ascribing TNF blockers to have a causal role in the development of lymphomas.
Placebo
controlled studies which were presented earlier have been small, and they have
had particularly very small follow-up times relative to the time period that
one might expect for a malignancy to develop.
The
manufacturer's pre- and post-marketing cohort studies have likewise been short
relative to follow-up times that we would expect for carcinogenesis.
We
have gone back to the post-marketing data, and this is new information which
isn't in your briefing document, because it is only been in the past couple of
months that we have been able to generate it out, on lymphomas reported to FDA
following TNF blockers from January of 1999 until December of 2002.
There
were 863 reports with medDRA terms, both specific terms and nonspecific
terms. We cast a wide net, looking for
lymphomas and TNF blockers. Four hundred
seventy-three of these were on patients who received Infliximab therapy; 390
were patients who had received etanercept therapy and who developed lymphoma.
We
went through these and found that, as we had expected, a large number of them
simply didn't have lymphomas, but there were 95 reports of biopsy proven
lymphoma diagnosed subsequent to Infliximab therapy, and 63 reports of biopsy
proven lymphoma diagnosed subsequent to Etanercept therapy. Together, these represent 158 cases that we
have of lymphoma that were subsequent to therapy with one of the TNF blockers.
Over
here on this side, 368 did not have lymphomas.
Eight had no biopsy. One lacked
temporality, and similar numbers for Etanercept cases.
Here's
how the cases marched out over time. You
can see that, since the licensure of these drugs, there were very few, and they
have risen throughout time. We would
expect, of course, that the distribution of these drugs has likewise increased
throughout this period of time.
A
little bit about these patients: most of
them had a median -- They had a median age of 64, but a pretty wide range of
age, and they were similar between the two drugs. Most of these patients were females.
The
indications were slightly different between infliximab and etanercept, as would
be expected by the diseases that they are licensed for. Rheumatoid arthritis, however, made up the
bulk in both cases. Infliximab also had
21 percent of the cases with lymphoma had Crohn's disease, and there were a
higher proportion of other diagnoses associated with Etanercept.
A
little bit about the histology of the 158 lymphomas, and this is really a
little bit, to underscore how incomplete MedWatch reports can be. Fully half of them had lymphoma. NOS is "Not Otherwise
Specified." And 26 of them had
non-Hodgkin's lymphoma, not otherwise specified. So this category we can't say very much more
about.
Fifteen
percent, we knew, were B-cell lymphoma but were not otherwise specified. Hodgkin's disease made up 20 of them, T-cell
lymphomas, mantle cell lymphoma, plasmacytoma and one Burkitt's cell lymphoma.
So
in conclusion on this topic of lymphomas and what the post-marketing data have
to say about it, they are poorly characterized.
It has really not been established if they are the same grade as the
general population, because so little has been described about them in the
reports. Histologically, they may be
consistent with lymphoma secondary to immunodeficiency, but at this point we
just don't have the information.
The
clinical trials, as Dr. Liang has already described, have found increases in
non-Hodgkin's lymphoma risks, but that was based on very few observations. The assessment is complicated by rheumatoid
arthritis confounded increases.
The
number of cases of lymphoma among persons taking Beta blockers is growing --
excuse me, TNF blockers is growing, and the FDA really needs the input from the
AAC to assess the causality and/or propose means to better evaluate the
causality.
Okay,
moving on here to what I consider the secondary topic of my talk, liver
failure. The reason for consideration of
it in this talk is that it is a signal for Leflunomide, and thus it is of
interest for completeness to look and see what was in the data on TNF blockers.
In
clinical trials also, some patients on Infliximab showed elevated increases in
liver enzymes, and I will show you that in just a moment. Here it is.
Infliximab mediated ALT increases:
If you compare placebo and Infliximab, here are two separate studies,
one study of rheumatoid arthritis patients on methotrexate, which is known to
increase liver enzymes all in itself, and one study of Crohn's Disease patients
without methotrexate.
We
can see that there are some fairly modest increases, 29 percent to 37 percent,
36 percent to 42 percent, in ALT. Now
you should note that most of these ALT increases were less than two times the
upper limit of normal, and there were no clinical sequelae in any of the cases
with these ALT increases.
A
little bit of the reporting, the cases that were reported through passive
surveillance now through the MedWatch program.
There were 134 reports to MedWatch citing Etanercept or Infliximab and
the MedDRA term that may have coded for liver failure. Then we reviewed those, much as we did the
previous ones.
Fifty
of these reports actually had well documented liver failure following an
anti-TNF therapy. But when we looked
more closely at these 50 reports, we found that fully 43 of the reports had
other proximal causes or other possible causes at least for their liver failure,
and only seven of them lacked another cause.
However, many of those seven were poorly described, and we have asked
for further information on them, and we are continuing to evaluate them.
Here
are those other causes. Thirteen were
associated with sepsis. Again, we can't
say that this wasn't an indirect cause of the TNF blockers, because sepsis may
well have been associated as an adverse event from the TNF blockers
themselves. Eight of them had
tuberculosis, in many cases disseminated tuberculosis, and were on INH
therapy. So there is another possible
cause. Ethanol, Graft-versus-Host
disease, viral hepatitis, other drugs which may cause liver failure, and other
causes among the remaining ones.
So
in conclusion on this topic of liver failure and the TNF blockers, liver
failure with TNF blockers appears to be a fairly rare event. while there are a large number of people on
TNF blockers, chance occurrence to explain this is pretty unlikely, because the
baseline rates are generally thought to be about one per million in the general
population for liver failure.
Still,
causality can't be ruled out, and some concern remains warranted. That concern is being addressed through
further clinical data which is pending on those remaining seven cases. Thank you.
CHAIRMAN
ABRAMSON: Thank you. Questions for Dr. Cote? Dr. Gibofsky?
DR.
GIBOFSKY: An extension of my previous
question to Dr. Liang: If you look at the 158 cases of lymphomas which were
aggregated into Crohn's Disease, rheumatoid arthritis and other, if you
separate them out by category, do any patterns emerge either in terms of
relationship to duration of therapy or onset since therapy was initiated?
DR.
COTE: No. No further patterns have emerged at this
point in relation to either of those two questions. In addition, that burden of disease, those
158 cases, were similarly shared between Etanercept and Infliximab.
CHAIRMAN
ABRAMSON: Dr. Jaffe?
DR.
JAFFE: Do you have any data on EBV
positivity, since EBV is often found in the lymphomas associated with
rheumatoid arthritis and other immunosuppressive agents?
DR.
COTE: It's a very good question. It is a reasonable question to address. We don't have the data. It could be reasonably ascertained by getting
the blocks and doing the tests.
CHAIRMAN
ABRAMSON: Dr. Blayney.
DR.
BLAYNEY: I think there is a great danger
to over-interpreting the data that you have.
In the MedWatch program, has there ever been any proof or any tests with
known adverse event in a well characterized population to try and understand
how much of that gets into the MedWatch database in any --
DR.
COTE: There have been some studies. There's a number that is bantered about as
ten percent. However, that number is
very subject to different influences, one of which is the adverse event of interest. Some adverse events are going to have a
higher proportion. Some are going to
have a lower proportion.
We
know that these 158 are the minimum number of cases which have occurred, but
what proportion of the total they may be is unknown.
DR.
BLAYNEY: And I think there's -- You
know, as these events become known among the users of these drugs, there's a
potential for ascertainment bias --
DR.
COTE: Absolutely.
DR.
BLAYNEY: -- in reporting.
DR.
COTE: As things get reported, more reports come in. You are absolutely right.
DR.
BRAUN: I'd just like to add to
that. My name is Miles Braun from
FDA. It is really hard to come up with a
rule of thumb about the proportion of reports that would be reported to FDA,
and there's been, in particular, work in the vaccine side that shows that it
could range from two or three percent up to around 70 percent, depending on
what the adverse event is, and different characteristics of the adverse events,
including the time between when the product is given and when the adverse event
occurs, and what the degree of recognition of the adverse event is.
So
that is -- It's a good question. It's
one of the limitations -- one of the multiple limitations of dealing with these
data.
CHAIRMAN
ABRAMSON: Yes, Dr. Krook.
DR.
KROOK: Kind of a follow-up to one of the
other questions. In the MedWatch
program, any spontaneous remissions as long as you've collected these numbers? I mean, I realize the data is incomplete, but
just as you get these, whether that is in those.
DR.
COTE: In all honesty, we haven't
reviewed the 158 series to know whether or not that is the case. It is something that we will do when we go
back and re-review it, and I'd be happy to let you know in follow-up.
CHAIRMAN
ABRAMSON: Dr. Jaffe?
DR.
JAFFE: As you presented the data, based
on the MedDRA culling about three-quarters of the cases were thrown out as not
being lymphoma?
DR.
COTE: The main reason is because we used
some very nonspecific terms for lymphoma, things like infiltrates and things
which were very nonspecific terms, in an effort to make sure that we caught as
many of the lymphomas which were in the MedDRA in the database.
So
that's the reason why a large number of -- large proportion were thrown out.
CHAIRMAN
ABRAMSON: Can I look at your slide 7 and
follow up on Dr. Gibofsky's question?
The accrual rate of cases with time could either be numbers of exposed
or a latency period of duration of
exposure.
DR.
COTE: Absolutely
CHAIRMAN
ABRAMSON: Do you have data on the
average time from the onset of treatment to the development of lymphomas?
DR.
COTE: We did try to look at that. Unfortunately, the data within the reports
wasn't sufficient for us to bring it forward.
Probably only 30 percent had the requisite data diagnosis of the
lymphoma and date of first treatment with the TNF blocker therapy.
In
going back to these patients -- and, of course, that is always an option to us,
both at the FDA level or at the manufacturer's level -- that information could
be obtained. It's information that we
wanted to see, too.
CHAIRMAN
ABRAMSON: Other comments? Dr. Krook.
DR.
KROOK: Taking the same question that you
just asked, and again this is all taking that same graph that you have, can you
put that against the use of one of these drugs that at the same time -- I mean,
these are cases reported. The amount of
drug being used is increasing.
DR.
COTE: We can, and probably the
manufacturers will show you information on the distribution of drug. It will be very similar. The slope of the curve will be very similar.
DR.
KROOK: That's what I thought it would
be.
CHAIRMAN
ABRAMSON: Okay. Thank you very much. The next speaker is Dr. Unger on congestive
heart failure.
DR.
UNGER: Good morning, everyone. This will
take a second to load. If I could talk
and chew gum at the same time, I could maybe introduce myself while I do this
and get started, but I'm going to wait.
DR.
WEISS: We have an old version of
PowerPoint. It's very slow in the
government.
DR.
UNGER: Again, I'm Ellis Unger. I am a medical reviewer and team leader in
the General Medicine Branch in the Office of Therapeutics in CBER, and I am
going to talk about anti-TNF alpha strategies in congestive heart failure, and
I am going to speak primarily on data form randomized controlled clinical
trials in heart failure patients, and I will spend a little bit of time talking
about some post-marketing reports for congestive heart failure.
The
cardiology community enthusiastically embraced the hypothesis of anti-TNF
strategies in congestive heart failure.
There were clinical observations of elevated TNF alpha levels in
patients with congestive heart failure, particularly patients with cardiac
cachexia.
There
were some preclinical data showing TNF alpha induced left ventricular
dysfunction and deleterious effects on left ventricular remodeling, and these
led to anti-TNF alpha hypotheses that TNF-alpha contributes to the morbidity of
congestive heart failure and that anti-TNF-alpha therapies would have salutary
effects in patients with congestive heart failure.
On
the basis of these hypotheses, a number of clinical trials were initiated, and
the ones that I am going to be talking about this morning are two randomized
trials with Etanercept and one randomized controlled study with Infliximab.
The
etanercept studies went by the acronyms "RENAISSANCE" and
"RECOVER." That is how I will
refer to them this morning. Because the
studies were so similar, they were regarded as sister studies. I will actually present the two of them
together.
RENAISSANCE
was conducted by Immunex in
Both
were Phase 2/3 studies, randomized, double blind, placebo controlled,
multi-center studies.
For
inclusion, patients had to have CHF on an ischemic or non-ischemic basis, an
ejection fraction less than 30 percent, symptoms of congestive heart failure
for at least three months, and New York Heart Association Functional
Classification 2, 3, or 4. Patients also
had to be receiving a diuretic and an ACE inhibitor.
Now
this is a somewhat complicated slide. So
bear with me. RENAISSANCE is shown over
here, and RECOVER is shown over here.
Both used Enbrel 25 mg SC, and placebo.
But the Enbrel was given on different schedules.
So
for RENAISSANCE Enbrel was given two times per week or three times per week,
two times per week being the recommended dose for rheumatoid arthritis. For RECOVER, which was the European study,
Enbrel was given once a week or twice a week.
The treatment duration was 24 weeks.
The
clinical endpoints were: First, a
clinical composite score, which was assessed at 24 weeks, that I will explain
momentarily; and a combined endpoint across both studies of mortality or
congestive heart failure hospitalization.
For that endpoint, the twice weekly and three times weekly groups were
combined, and the once weekly group in the European study was not included.
This
clinical composite score was regarded as worse if a subject died, if they were
hospitalized for heart failure, if they had worsened New York Heart Association
functional classification, or if they global assessment, judged by the subject,
was moderately or markedly worse.
The
composite score was improved if, first, the clinical composite score was not
worse, and New York Heart Association functional classification was improved,
or the global assessment was moderately or markedly improved.
The
third possibility was unchanged, which was the categorization that the score
was neither better nor worse.
Now
I'll go into the results of these two studies.
First, both studies were stopped in March of 2001. At a planned interim review, the DSMB
recommended that both studies be halted, because the pre-specified results
indicating futility had been observed.
At
that point, because the studies did not initiate enrollment at the same point
in time, the median follow-up in RENAISSANCE was 12.7 years, and for RECOVER --
months, excuse me -- and for RECOVER, 5.7 months. So approximately a twofold difference in
terms of the data for the two studies.
The
baseline characteristics for RENAISSANCE were fairly typical of the congestive
heart failure patient population. I
point out that approximately one-quarter of the patients were functional class
II. Half were functional class IIIa. Another quarter were a functional class IIIb,
and a very slim minority were function class IV.
The
treatment groups were very well balanced with respect to demographic and
baseline characteristics, and I won't show them, but I will point out that
there were four notable exceptions, and I point them out because they all tend
to favor the placebo group.
So
for the placebo group on average, the baseline blood pressure was slightly
higher. The six minute walk was slightly
longer. Antiarrhythmic use was less
frequent, and atrial fib or flutter was less frequent. So the imbalances were small, but all would
be associated with a more favorable prognosis in the placebo group. That's why I mention them.
For
RECOVER, the European study, again patients were very typical congestive heart
failure patients, and the breakdown by New York Heart Association functional
classification was quite similar to the North American study.
This
is the primary endpoint, week 24, for RENAISSANCE. The results are shown with -- Worse results
are shown in blue, improved yellow, and no change is white. The results are most notable for an increased
percentage of patients who were in the "Worse" category for the twice
weekly and three times weekly Enbrel compared to placebo.
These
are the same data for RECOVER, the European study. In this case, the data were most notable in
the twice weekly Enbrel group, a trend toward increased number of patients in
the "Improved" category. So
there seemed to be a difference.
The
other co-primary endpoint was all-cause mortality and congestive heart failure
hospitalizations across both studies, again the twice weekly and thrice weekly
Enbrel groups. You can see that there is
a trend favoring placebo in terms of a worse outcome in patients who received
Enbrel.
I
will tell you that the difference between the groups was mostly driven by a
difference in mortality and not congestive heart failure hospitalizations. So we are going to look more in depth at the
mortality.
This
is the mortality data for RENAISSANCE.
The white line represents the placebo group, yellow twice weekly, and
blue thrice weekly Enbrel. You see the
difference here between the groups. The
percent mortality was at 14.2 in the placebo arm versus 17.9 in the twice
weekly Enbrel and 19.8 in the three times weekly Enbrel group. This was concerning to us.
For
RECOVER, you see kind of a different trend.
Actually, the placebo patients looked to be worse than the patients on
Enbrel. However, because of the
difference in length of data, length of follow-up, I will point out that at
this point only one-fourth of the patients were still at risk. So, really, the data are quite sparse out
here.
Given
the differences between the outcomes of the two studies, we looked at some of
the difference in the patient populations to try to identify factors that might
impart a worse prognosis in patients with heart failure receiving Enbrel, and
there were some differences in terms of race, in terms of blood pressure,
potassium sparing diuretic use, digitalis and lipid lowering agent use.
I
will tell you that none of the exploratory analyses really identified factors
that appeared to put patients at increased risk on Enbrel with heart
failure. But there was one subgroup
analysis that I would like to go over with you.
Again,
this is a post hoc subgroup analysis,
and it has its limitations, but actually, when I did this analysis, my
hypothesis was that patients who have more severe heart failure, functional
class IIIb, might be more susceptible and vulnerable to the effects of Enbrel.
In
fact, that hypothesis was not borne out.
For patients who were more severely affected with heart failure, there
appears to be no difference between Enbrel and placebo. And in fact, the difference in the study was
driven by the difference in function class II patients.
The
conclusion from this is simply that we cannot provide reassurance to physicians
that patients with milder forms of heart failure are at lower risk of Enbrel
induced deleterious effects.
It
is worthwhile to go over some of the SAEs and AEs, basically, to look for clues
in terms of the mechanism. One would
wonder whether Enbrel had deleterious effects in terms of rhythm, in terms of
ischemia, maybe in terms of hemodynamic factors, maybe negative inotropic
effects.
To
make a long story short, we don't really find any clues in looking at the
adverse event reports that would point us in the direction of one mechanism or
another.
The
selected AEs are interesting in that we see a trend toward an increased number
of a couple of the AEs. Realize, these
are selected. Dizziness and chest pain
seem to be more frequent in patients who received Enbrel than in placebo
patients, but again they are selected.
In
terms of SAEs, the main one was increased congestive heart failure, which would
be as one would expect.
So
for etanercept in congestive heart failure, there is no evidence that
Etanercept is beneficial in congestive heart failure. The data suggest harm, though the results are
not conclusive.
The
key finding of concern was a trend toward higher mortality in Etanercept
treated subjects in RENAISSANCE. This
concern was heightened by the apparent dose response relation.
The
results of RECOVER do not substantiate the findings of RENAISSANCE with respect
to Etanercept induced mortality in congestive heart failure. And the greatest concern was for an Enbrel
dose higher than that currently licensed for rheumatoid arthritis in the
The
data do not suggest a specific mechanism of action leading to Etanercept
related adverse outcomes in the congestive heart failure patient
population. Exploratory analyses failed
to identify specific factors associated with increased risk of adverse events.
In
particular, patients in RENAISSANCE with milder congestive heart failure did
not appear to be at lower risk of adverse outcomes.
So
from labeling, there is no basis to provide, first, a measure of reassurance
for patients with mild forms of congestive heart failure and, second, a listing
of factors that appear to predispose to worsening congestive heart failure.
Now
I will move to Infliximab in congestive heart failure. There is one study conducted under the
acronym "ATTACH." This was
done by Centocor. This was a Phase 2
pilot trial, randomized, double-blind, placebo-controlled, multi-center study.
One
hundred fifty subjects were randomized equally to Infliximab 5 mg/kg at 0, 2
and 6 weeks or 10 mg/kg, or placebo on the same schedule.
The
inclusion criteria included symptoms of congestive heart failure for three
months, New York Heart Association functional class 3 or 4, ejection fraction
less than 35 percent, and patients had to be receiving a diuretic and ACE
inhibitor.
The
primary endpoint was the same, clinical status at 14 weeks improved, worse, or
unchanged. Here are the data.
There
are approximately 50 subjects per group.
Again, the patients who had a worse clinical status are shown in blue,
and you can see eight percent in the placebo arm versus ten percent with the 5
mg/kg, 22 percent for 10 mg/kg.
The
silver lining was that there appeared to be somewhat more patients who were
improved, but that was offset by the patients who were worse. Those are the data at 14 weeks. I should have mentioned, that was a primary
endpoint.
Another
endpoint, a secondary endpoint, was the clinical status at week 28, and the
trend basically continued, 14 percent versus 16 versus 31 percent worse in
clinical status at week 28.
The
sponsor collected all-cause mortality through one year, and there were four
deaths in the placebo group, four deaths in the 5 mg/kg group, and eight deaths
in the 10 mg/kg group.
On
the basis of the interim data, a Dear Healthcare Professional letter was issued
on
In
part because the mortality rate in the placebo arm and the 5 mg/kg arm were the
same, one might conclude that, in fact, the 5 mg/kg dose of Infliximab is not
deleterious. But the selected AE
analysis here doesn't bear that out.
You
will notice, for dizziness -- these are symptoms -- Some of them are a little
bit soft in terms of indicating heart failure, but I think you will agree, they
could point in the direction of heart failure.
The incidence of dizziness, 4.2 percent, versus 31.4, versus 20;
dyspnea, 12.5, 19.6, 24; angina, obviously, points toward an ischemic
mechanism: 2.1 versus 5.9 versus 4.8;
and hypotension 5.9 and 8 versus zero.
So
it suggested a number of mechanisms, maybe hemodynamic effects, maybe ischemic
effects, but the whole thing is tempered by the fact that we have very small
numbers. But I think, in all, one might
conclude that, in fact, the 5 mg/kg dose is not clean. There seem to be deleterious effects at this
dose in patients with congestive heart failure.
So
for Infliximab there is no evidence that it is beneficial in patients with
congestive heart failure. Although the
numbers of subjects treated are small, there is a strong trend suggesting
increased mortality in congestive heart failure patients treated with
Infliximab.
The
data do not show an increase in mortality with the 5 mg/kg dose. However, adverse event data suggest that the
5 mg/kg dose is deleterious. The
mechanism underlying this apparent effect is unclear.
When
we have these data in hand, it caused us to then query our post-marketing
reports in terms of congestive heart failure, and that was done by
epidemiology. They found 51 case reports
as of February 2002. So it was a year
ago. Thirty of these were for
Etanercept, 21 for Infliximab, and of the 51 cases 42 reports were for new
onset congestive heart failure. Half of
these had no identifiable risk factors, and nine were reports of the congestive
heart failure exacerbation.
Median
age was 64 years. Median time to onset
was 3.5 months, and 20 percent of these subjects or patients were less than 50
years old.
For
those patients less than 50 years old -- there were ten of them -- six had
received Infliximab and four Etanercept.
The median ejection fraction was 20 percent. Three had underlying risk factors for
congestive heart failure. Ten had none
reported, and after discontinuation of the TNF antagonists and institution of
heart failure treatment, three reported complete resolution, six improved, and
one died.
I
think one has to consider the post-marketing data with the limitations of
passive surveillance in mind. But
nevertheless, they are interesting.
So
in summary, overall the significant overlap between congestive heart failure
and rheumatoid arthritis in the general population and, to a lesser extent, in
congestive heart failure in Crohn's Disease.
Data from the randomized controlled trials in the CHF population raised
concerns about the safety of Infliximab and Etanercept.
Post-marketing
data raised concern regarding new onset congestive heart failure. Comprehensive analyses of the randomized
controlled trial databases of all three TNF blockers may be warranted, and the
specific language for labeling is presently under discussion. Thank you very much.
CHAIRMAN
ABRAMSON: Thank you. Questions for Dr. Unger? Dr. Blayney.
DR.
BLAYNEY: I understand these agents can
cause lymphoma and opportunistic infections which are adverse events in the
clinical trials. Did the cardiologists
not report them or were they so low that they didn't make your list of selected
adverse events or is there some other reason you could help me see why those
were absent in your slides?
DR.
UNGER: Because basically the orientation
of the analysis was congestive heart failure, but the data are there and have
been analyzed. I don't have any slides
to show you, and I would be reluctant to give you the information off the cuff.
DR.
BLAYNEY: Perhaps we could -- Can we shed
some light on that issue or maybe later on today?
DR.
WEISS: Perhaps, actually, when we get to
the discussions in the afternoon, we can pull out some of the information that
might help address your questions.
CHAIRMAN
ABRAMSON: Dr. Ilowite.
DR.
ILOWITE: In the RECOVER trial where they
got weekly doses, the patients -- subjects who got weekly doses, was there any
temporal relationship of worsening heart function with the dose, because you
would expect the drug would be gone toward the end of the week.
DR.
UNGER: The study really wasn't designed
to capture that kind of information. You
can imagine, if a patient comes once every week or once every three -- I can't
remember what the exact schedule was, but they weren't coming in more than once
a week. So --
CHAIRMAN
ABRAMSON: Your penultimate bullet point
there -- I assume you are analyzing the clinical development programs?
DR.
UNGER: Yes, we are. We debated whether we should promise that we
were doing that, but we are doing it.
DR.
SIEGEL: I should mention that we have
looked for cases of CHF in the clinical trials for rheumatoid arthritis, and no
signal emerged. But we want to go back
and look in a more comprehensive way in case there's some signal that is more
subtle that might have been missed.
DR.
UNGER: I will tell you that, when I went
through the adverse event line listings, I came upon patients who had dyspnea
on exertion which was categorized as a pulmonary problem, and peripheral edema
which was categorized as a body total or metabolic or whatever.
These
were not put together as congestive heart failure, and that is pretty
typical. So we are going to put them
together and see what kind of signals we come up with.
CHAIRMAN
ABRAMSON: Okay, thank you.
DR.
ILOWITE: In the Infliximab trials, was
there a temporal relationship between the infusion, during the infusion or
shortly after the infusion, and worsening cardiac function? Is that data available?
DR.
UNGER: Again, the study wasn't really
designed to capture that. Vital signs
were looked at, and there were no signals.
There were no striking hemodynamic effects from Infliximab or
Etanercept. That was something that was
of concern in terms of whether it may have, you know, a direct, immediate
hypotensive effect, and that wasn't apparent.
CHAIRMAN
ABRAMSON: Dr. Elashoff?
DR.
ELASHOFF: For a non-M.D., with respect
to the CHF cases in the patients under 50 years old, would it be surprising
that so many improved, but would that be what you would expect with cases like
this?
DR.
UNGER: I think it's pretty much what you
would expect. Yes.
DR.
WEISS: Don't forget, they also -- I mean
they withdrew the drug, and then they also had heart failure medication
instituted, and again these are post-marketing reports with the sketchiness
that is there. So we don't know if it
was just, you know, a mild diuretic and then they felt better or, you know, how
extensive exactly that their treatments needed to be.
CHAIRMAN
ABRAMSON: Okay. Dr. Makuch?
DR.
MAKUCH: You indicated that there was a
trend toward increased mortality in the RENAISSANCE trial, and it was
heightened by the apparent dose response relationship. The question I have is
what happened to the 1x? I was wondering
if the 1x group would have perhaps enhanced your ability to see a dose response
rather than just the way that you looked at the study results today.
DR.
UNGER: Well, the patients who received
1x did about as well as placebo in the European study. There is somewhat of a danger in combining
the data because of the different length of follow-up, because they are different
studies.
The
sponsors did those analyses. I don't
have that. So I'd like to show you that
slide right now. Unfortunately, I don't
have it. The sponsor may have it.
Basically,
when you look at that, you know, with its limitations, I think it just
reinforces the dose response, although it is not as apparent as it was if you
look at the North American data on its own.
DR.
MAKUCH: Thank you.
CHAIRMAN
ABRAMSON: Yes, Dr.
DR.
ANDERSON: I have a question which comes
out of Slide 23 which compares the subject populations. In view of the quite large difference between
the RENAISSANCE and RECOVER populations in their other medications, in
particular, potassium sparing diuretic, I was wondering were there any
subanalyses -- exploratory analyses done that took into account the other
medications that the patients were on?
DR.
UNGER: Yes, absolutely. We looked at patients in the North American
study who had received diuretics and not received diuretics, and received
potassium sparing diuretics and not, and found no signal there. We were hopeful that we would find something,
but we didn't.
CHAIRMAN
ABRAMSON: If there are no further
questions, we thank the presenters for their very lucid presentations, and we
will take a 15-minute break. I'm sorry,
Dr. Jaffe?
DR.
JAFFE: If I could just back up here, Dr.
Cote, I have one question for you before you run off. Of the 158 patients with lymphoma, how many
of those patients were also on methotrexate or other immunosuppressive agents?
DR.
COTE: I don't have that information
right here. I'm sorry.
CHAIRMAN
ABRAMSON: Okay. So we will reconvene at a
(Whereupon,
the foregoing matter went off the record at
CHAIRMAN
ABRAMSON: We are about to begin the
second session this morning, and the first presentation will be from Abbott
Laboratories. Dr. Lefkowith will be the
presenter. In just a short moment, we
will get started, Jim, whenever you would like.
Dr. Lefkowith.
DR.
LEFKOWITH: Good morning. I am Dr. Lefkowith, and on behalf of Abbott
Laboratories, I would like to thank the committee and the agency for this
opportunity to present our data on adalimumab, now known by the trade name
HUMIRA.
After
a brief introduction, I will cede the podium to Dr. Fischkoff, who directed the
clinical program, who can present to you our data on adalimumab. With us also this morning is Dr. Bob Tarone
of the International Epidemiology Institute, who will detail some of the
information behind the SEER database and provide the calculations for the
standardized incidence ratios, for example, so you can understand the analyses
better behind malignancy and the lymphoma data specifically.
I
will end briefly with some comments regarding our recommendations for your
consideration.
With
us also this morning are Doctors Paulus and O'Dell, who are made available to
the committee as practitioners of the art as well as experts in the field.
Adalimumab
(HUMIRA) is an IgG1 kappa human monoclonal antibody derived using phage display
technology. It neutralizes specifically
human TNF-alpha with high affinity and specificity. It resembles, for the most part, endogenous
IgG with a half-life of approximately two weeks.
Currently,
HUMIRA or adalimumab is indicated in the treatment of adult RA in patients with
moderate to severe disease who have inadequately responded to prior therapy
with DMARDs.
It
treats both the signs and symptoms of this disorder and inhibits the progression
of structural damage as assessed radiographically. It can be used either alone or in combination
with other DMARDs such as methotrexate, and the recommended dose is 40
milligrams every other week.
Contained
within the package insert are certain specific warnings regarding serious but,
nonetheless, uncommon side effects. IN
particular, there is a boxed warning regarding tuberculosis which contains
within it guidance to the practitioner regarding the appropriate screening
procedures prior to the institution of therapy.
There
are also warnings within the package insert regarding serious infections,
particularly tuberculosis, demyelinating disorders, malignancies, and
specifically lymphomas and, obviously, our presentation will focus largely on
this latter subject.
I
think it is well to briefly review some of the sources of variability within
the data. IN particular, you will hear a
variety of presentations today which use different sources for data to base
their calculations for rates on. All
data are unique in that we are relying only on controlled trials for our rate
calculations for serious adverse events.
Registries
represent a less well controlled environment, nonetheless useful, and
post-marketing surveillance, obviously, is more qualitative and useful for
signaling in terms of safety.
There
are also important patient variables, particularly baseline demographics of the
patients of interest, age, sex, race, and geography being paramount among those
considerations. Moreover, disease
severity or duration, as you have heard, are important considerations as well.
I
would now like to turn the podium over to Dr. Fischkoff.
DR.
FISCHKOFF: Good morning. My name is Steven Fischkoff, and it is a
pleasure to have the opportunity to present to you the clinical data from the
adalimumab development program.
What
I will be presenting today is, first, some information about the structure and
scope of the clinical development program, and also the efficacy data that
supported the registration of HUMIRA. In
addition, consistent with the focus of this meeting, the bulk of the
presentation will be on safety issues, particularly a number of issues that
have been associated with the class of TNF antagonists, specifically
tuberculosis, CNS demyelination, congestive heart failure, and malignancies and
malignant lymphoma.
In
addition, Abbott is committed to continue to study the safety of HUMIRA in the
post-marketing period, and understands the importance of those
commitments. I will also go through the
structure of the program to look at this in the post-marketing period.
The
overall program that was filed with the dossier consisted of approximately 2500
patients treated with adalimumab for approximately 5000 patient years. The data that we will be presenting today has
a cutoff of
Twenty
studies in rheumatoid arthritis were filed with the BLA, of which four are
pivotal, and we will go into some more detail in a few moments. Approximately 1400 patients received
adalimumab in these clinical trials.
In
addition to having a large number of patients available for analysis, the
length of follow-up was also long.
Approximately 2000 patients had at least one year of follow-up, and the
overall median exposure to adalimumab in the studies was two years. IN fact, about 40 patients are now in their
sixth continuous year of adalimumab treatment.
Four
studies were considered pivotal and are shown here. Two of the studies were conducted in patients
taking adalimumab with concomitant methotrexate, one in patients taking
adalimumab as monotherapy, and one which I will discuss in a little more detail
in a manner that was designed to simulate clinical practice.
The
first study, DE009, which is also known in the literature as ARMATA, randomized
approximately 300 patients to either placebo or one of three doses of
adalimumab. The primary endpoint for
this study was the signs and symptoms of rheumatoid arthritis, with the ACR20
score at six months being the primary endpoint.
The
next study, DE019, randomized approximately 600 patients to either placebo or
one of two doses and schedules of adalimumab.
This study also had a signs and symptoms endpoint at six months, the
ACR20, but in addition there were two other endpoints, one relating to disability
at one year as measured by the disability index of the HAQ at 12 months, and
also the ability to inhibit the radiographic progression as measured by the
modified total Sharp Score, again at 12 months.
I will show you this data in a few moments.
Study DE011 was the one study of the four
studies that was conducted in
As
you heard before, at the end of the Phase 2 portion of the program, FDA
recommended that we increase the overall size of the program so that
approximately 1,000 patients would be available with a year of treatment at the
recommended dose and schedule. As a
result of this, we added study DE031 which enrolled approximately 600 patients.
This
study was designed to simulate clinical practice as best as possible in a
clinical trial, because it allowed patients to continue their preexisting
DMARDs rather than being washed out.
Patients enrolled in the study were taking between 0 and 4 concomitant
DMARDs.
In
addition, they were allowed to increase a DMARD, to increase a corticosteroid
or add a DMARD during the course of the trial and remain on the trial. We felt that this would be best to simulate
actual clinical practice.
The
study was powered so that we could pick up a one percent adverse event rate
with 95 percent confidence at six months in either of the treatment
groups.
The
average age of the patients was 55 years.
This was a late stage patient population with a mean duration of disease
of 11 years. We have an ongoing study in
early RA, but there is no data to present today from that study.
The
mean number of prior DMARDs was three, and the patients also had active disease
with a mean tender joint count of 30 out of a possible 68, a mean HAQ of 1.6,
consistent with moderate to severe disability, and also a mean CRP of 2.8 with
an upper limit of normal of 0.8.
In
particular, the one study, DE011, which was the monotherapy study conducted in
Europe, enrolled the most advanced and sickest patients with a mean prior DMARD
value of 4 and the highest tender joint count, HAQ, and CRP.
I
will now show you the signs and symptoms efficacy data that supported the
registration. The ACR20 was the primary
endpoint and, as can be seen, in all four pivotal studies there's a highly
statistically significant improvement in patients receiving adalimumab,
including even in study DE011 which enrolled the sickest patients and the most
advanced patients. Again, this was also
highly statistically significant.
The
onset of efficacy was rapid. In study
DE009, efficacy was statistically significantly improved as early as one week,
and remained statistically significantly improved out to six months.
In
study DE019, which went out to a year, the efficacy was again statistically
significant all the way out to a year, based on the ACR20 score. In addition, the HAQ score, which is not
shown here, was also highly statistically significantly improved compare to
placebo out at one year.
Now
the ACR20 score is clearly important for regulatory approval, but patients also
want to achieve higher degrees of relief, and the ACR50 and the ACR70 score are
also indicators of this higher degree of relief.
As
can be seen here again, in the studies with concomitant methotrexate, in the
study with monotherapy and in the study with the concomitant DMARDs, there was
a highly statistically significant improvement in the ACR50. Again, the ACR70 shows the same pattern with
statistically significant improvement compared to placebo in all four studies.
The
radiographic progression and the ability to inhibit it was measured in study
DE019. In this study, approximately 600
patients were randomized to receive either placebo or adalimumab, and X-rays
were taken at baseline, at six months, and at one year.
As
can be seen in the patients receiving placebo, there was a continuous and
linear progression in the modified total Sharp Score over one year. However, in patients receiving adalimumab
there was a statistically significant inhibition in the radiographic
progression at both time points.
Looking
at the two subscores, joint erosion and joint space narrowing, again there is a
linear progression over one year in patients who received placebo, but there is
a highly statistically significant improvement or inhibition of progression in
patients who receive adalimumab.
Disability
is another important feature of rheumatoid arthritis, and we used the HAQ --
the disability index of the HAQ to look at that. At six months in all four of the pivotal
trials, again, there is a highly statistically significant improvement compared
to placebo, and this improvement exceeds what is recognized in the literature
as the minimum clinically important difference of 0.22. In fact, DE009 the improvement in the HAQ was
statistically significant at two weeks.
So
we summarize about the efficacy of adalimumab, that it reduces the signs and
symptoms of rheumatoid arthritis as measured by the ACR20/50/70 score. It also inhibits the progression of
structural damage of rheumatoid arthritis as measured by the total Sharp Score
and also the subscores, joint erosion and joint space narrowing.
It
provides rapid onset and durable relief of rheumatoid arthritis, and also, as
measured at six months and at one year, there is an improvement in the
disability index of the HAQ.
There
are a number of safety issues that have been associated with the class of TNF
antagonists, and these are listed here.
First with tuberculosis.
Tuberculosis, as has been described earlier, has been seen with TNF
antagonists and, certainly, there is preclinical data suggesting that in a
number of animal models there is decrease in host resistance to tuberculosis
that can be seen.
In
some cases, there is a higher than expected number of patients who present with
either a miliary pattern on chest X-ray or extrathoracic presentation.
It is possible that the true incidence may be underestimated by
post-marketing reports for the reasons that were cited earlier and, as we will
show you in a bit, geographic and patient demographics can also greatly influence
the incidence of tuberculosis that could be seen.
As
a result of all this, clinicians are being alerted to the possibility of
tuberculosis in patients receiving this class of drugs, and certainly,
screening for tuberculosis has been recommended and has become standard
practice.
In
the adalimumab clinical program, there were 13 cases that were seen in patients
who received adalimumab. They were not
distributed geographically evenly. Six
were in Germany, one in each of four other European countries, two in the
United States, and one in Canada.
In
addition, there were three cases of tuberculosis in patients who were not on
adalimumab therapy, one in a patient receiving placebo, and two in patients who
had been off adalimumab therapy, but we had long term reports from their
physicians. Two of these cases were in
Germany, and one of them was in Italy.
This may represent a background incidence of tuberculosis in this
population.
The
peak incidence of tuberculosis was between three and eight months of treatment,
although there were infrequent cases out after a year. All of the patients presented today have
recovered with standard anti-tuberculous therapy, and there were no deaths.
We
looked again at the impact of screening, first within the pivotal trial program
and its follow-up and then in the open-label extension. I have shown before in the early studies,
Phase 1 and 2, screening was not yet implemented, and we had eight cases of
tuberculosis.
Later
in the Phase 3 program, we instituted screening with either our European study,
exclusion from the study if the chest X-ray was positive, or in the United
States and Canadian studies a recommendation but not an insistence on
prophylaxis if the PPD was positive.
In
the larger number of patients, there was only one case of active tuberculosis,
and this particular case was a patient who was PPD and chest X-ray negative at
baseline, but on presentation of active disease was positive for both,
suggesting that this is a primary case of tuberculosis.
Dr.
Liang referred to five cases of tuberculosis after the institution of
screening. This is one, and there were
four additional cases that were seen in the open-label extensions. Two of these cases had evidence of latent
tuberculosis infection at baseline but, for one reason or another, one because
of a change in the recommendations, and one because the investigator chose not
to, these patients were not screened, and potentially could have been
prevented.
I
will move on to CNS demyelination. In
the adalimumab clinical program, there were four cases that were seen. One of them presented as optic neuritis. Three of them presented with paresthesias. Of
these three cases, one of the patients had a prior diagnosis of probable
multiple sclerosis in the past.
All
of these cases resolved. The optic
neuritis case resolved on high dose corticosteroids. One of the paresthesia cases resolved
partially with Copaxone, and two resolved completely spontaneously.
Congestive
heart failure was a subject of discussion this morning. Abbott has not done specific trials in
patients with congestive heart failure, nor does it intend to. But as suggested before, we have looked into
our RA patient database to see what signals there might be.
In
the pivotal studies there were seven patients with a prior diagnosis of
congestive heart failure who were enrolled and received placebo, and 18
patients who were enrolled and received adalimumab. None of these patients suffered a relapse
during the pivotal portion of the studies.
In addition, there were patients who did
not have a prior diagnosis of congestive heart failure, but as can be seen, the
number of patients who developed new onset heart failure appears to be balanced
between active and placebo.
I
will now move on to malignancies and malignant lymphoma.
Based
on the literature, the impact of TNF antagonism on the risk of developing a
malignancy is unclear, because there are some studies that suggest that the
risk could be increased, and some studies that suggest that the risk could be
decreased.
Specifically,
TNF is involved in the immune surveillance for cancer in the body, and it is
also known that supraphysiologic -- in other words, pharmacologic -- doses of
tumor necrosis factor can induce regression of established tumors.
On
the other hand, there are also studies showing that TNF deficient mice are
resistant to skin carcinogenesis, and TNF is also a growth factor for a number
of human lymphoma and leukemia cell lines.
To
look at the potential impact of adalimumab on cancer risk, we used the
1992-1999 SEER database, and we used a matched patient population, matching for
age, sex, and race. Based on this, we
would expect to see 45.5 cancers in the treatment period, and 46 were observed.
Therefore,
the standardized incidence ratio, meaning the ratio of the number of cases
observed to the number of cases expected, was one with a confidence interval of
0.7 to 1.3.
We
looked to see if there were any particular types of tumors that had an
increased incidence based on their SIRs, including lymphomas and common types
such as those shown here. As can be
seen, with the exception of malignant lymphoma which had a confidence interval
that excluded one, the other types did not show any signal of a potential
increase in the incidence of those cancers.
We
also looked over time, and with up to five and a half years of follow-up it
appears that the risk of developing a cancer is constant over time, and there
is no evidence of either early onset of cancers or any acceleration in the rate
of developing a malignancy.
Malignant
lymphoma is different, because as we have heard this morning, there have been
multiple reports in the literature that the incidence in patients with
rheumatoid arthritis is elevated. And as
can be seen, there are a number of large patient based studies. There are some case controlled studies as
well and, as can be seen here, the standardized incidence ratio or the odds
ratio from these studies varies somewhere between 2 and 8.
One
study that tried to pick this apart was the study of Baecklund et al. that looked at the odds ratio as
a function of level of disease activity.
Baecklund found that there was a fairly strong correlation with higher
levels of disease activity being consistent with markedly elevated incidence of
malignant lymphoma.
If
you use the criteria that Baecklund et
al. used to assess patients, what they did was they took a measure based on
erythrocyte sedimentation rate, giving patients from 1 to 3 points, the number
of swollen and tender joints, adding an additional 1 to 3 points, and the
physician's global assessment of disease activity, again 1 to 3 points. So that a score would be somewhere 3 and 9.
the
mean of these scores from the visits was taken, and then this chart was used to
assign patients to low, medium or high disease activity, and that was the score
that was shown on the previous slide.
Based on this classification, the majority of patients in the adalimumab
program would be medium to high.
There
were nine cases of non-Hodgkin's lymphoma and one case of Hodgkin's disease,
for a total of ten, that were seen in the adalimumab clinical development
program. Calculating the standardized
incidence ratio, it was 5.5, which is consistent with the odds ratio of 5.4
that has been seen for patients with moderate -- with medium levels of activity
of their disease.
One
of the questions that the committee has been asked is to discuss the tumor
types, the cell types. So we have broken
this down, first by the cell type here, and we have compared two studies from
the literature that looked at the distribution of tumors, lymphomas, that were
seen in patients with rheumatoid arthritis.
In
our program 80 percent of the tumors were B Cell type, one was T Cell type, and
one was Hodgkin's. This is certainly
consistent with the prevalence of B Cell lymphomas that's seen in these
patients.
Looking
at the histology and comparing it to the rates that were described in the same
two publications, as you can see, the rates of each of the different histologic
types again matches very well with what was expected in the literature from
patients who have rheumatoid arthritis.
This
is the detailed breakdown of the patient characteristics. What I would like to point out is that in
these patients the mean age was 63, which is greater than the overall mean age
of the population of 55, and the mean number of years of RA was 12 1/2, greater
than the mean duration of RA of 11 that was seen in the overall population,
consistent with age and duration of RA being risk factors for the development
of malignant lymphoma.
Looking
again to see if there was any influence of time on the risk of developing
lymphoma, in this Kaplan-Meier analysis, again, we see no early onset of
malignant lymphomas, and we see no accumulation or consistent with cumulative
toxicity.
So
regarding safety, we conclude that TNF antagonists, including adalimumab, have
been associated with cases of active tuberculosis. Screening appears effective at reducing the
incidence of active tuberculosis and has become standard of care.
Rare
cases of CNS demyelination have been observed, and the malignancy rate that we
saw in the adalimumab clinical program is consistent with a matched, based on
age, sex and race, general population.
In addition,
the lymphoma rate is higher than the general population, but is consistent with
an RA patient population matched for disease activity.
Abbott
is committed to continuing to study the safety of adalimumab in the
post-marketing period and has committed to the following programs:
Number
one: Abbott is committed to continue
long term safety trials, which currently consist of approximately 1700
patients, for a total of five years.
These will be done under completely monitored conditions. This will increase the overall size of the
safety database by a factor of two but, more importantly, will increase by a
factor of greater than 10 the number of patients that have been followed for up
to five years.
This
will enable us to precisely calculate incident rates of adverse events of
interest, because we will be fully capturing all events and fully monitoring
all patients.
We
will supplement this with the European registry, which will enroll
approximately 3000-5000 patients, some of them coming from expanded access
programs. This will provide a large
supplemental experience with which we may hope to detect new rare adverse
events.
Abbott
is either conducting or will shortly conduct studies in some additional
indications, as shown here. We are
conducting studies in juvenile rheumatoid arthritis and early rheumatoid
arthritis. Studies are ongoing in
Crohn's disease and will shortly start in psoriasis, psoriatic arthritis and
ankylosing spondylitis.
In
addition, despite the limitations discussed before about spontaneously reported
adverse events, Abbott will still continue to collect them, and this may allow
us to detect potential new rare signals or perhaps changes in pattern that are
consistent with changes in medical practice.
Our
overall assessment of the risks and benefits of adalimumab is as follows. Adalimumab is effective in reducing the signs
and symptoms of rheumatoid arthritis and inhibiting the progression of joint
destruction.
TNF
antagonists have been associated with rare cases of tuberculosis and CNS
demyelination, and guidance is provided to both the patient and the
practitioner in the various package inserts.
Adalimumab
does not appear to contribute to the increased risk of cancer of malignant
lymphoma, based on the information that I have shown before, in the RA patient
population; and the benefit risk assessment is, therefore, quite high in favor
of adalimumab, and Abbott believes that this represents a significant
contribution to the care of RA patients.
I
will now turn the floor over to Dr. Robert Tarone who will go through in some
detail the methodology that is used for calculating the standardized incidence
ratios.
DR.
TARONE: I want to briefly describe the
calculation of standardized incidence ratios or SIRs, and comment on their use
in evaluating cancer in clinical trials.
The
standardized incidence ratio is an estimate of the relative risk of cancer in a
defined cohort followed for a specified period of time. Relative means relative to the cancer risk in
the general population from which the cohort was derived.
Now
the SIR is often represented as 0 divided by e, and that reflects how it is
calculated. The SIR is the observed
number of cancers in the cohort divided by the number of cancers that would be
expected if the cohort members have the same cancer risk as the general
population.
Now
to compute this expected number of cancers, we obviously need to have good
estimates of age-specific cancer rates for the general population, and for the
adalimumab trials we used the SEER database, the National Cancer Institute SEER
program.
This
data comes from population-based cancer registries. What that means is that SEER tries to
ascertain every single primary cancer diagnosed in the catchment area of the
SEER registries, and these catchment areas are defined by county or state
lines.
This
is important, because that means that SEER can get form the Census Bureau very
accurate estimates of the population size at risk by county and state for the
different age groups, which allows them to have the denominators needed to
calculate the age-specific cancer rates.
Now
SEER does not collect data on basal cell
or squamous cell skin cancers, and it does not collect data on metastases,
primary cancers only.
There
are currently 11 SEER registries, and there have been since 1992, and they
cover approximately 14 percent of the U.S. population. Now just for the record, very shortly there
is going to be an expansion of SEER for future applications. 2003 may be a slight optimistic. Actually, next month SEER will report the
incidence data for the year 2000. It is
delayed somewhat, because they have had to make adjustments to the denominators
based on the 2000 Census.
So
probably in early 2004, the 2001 incidence data will be reported, and that will
be based on four additional cancer registries.
After that, SEER will cover 26 percent of the U.S. population, and these
registries were added with minorities in mind.
In fact, there will be 24 percent coverage of African Americans, 44
percent of Hispanics in the United States, and 59 percent of Asian
Americans.
For
our current purposes, all we really need to know -- What is important is that
we can get sex-specific, race-specific, age-specific cancer incidence rates
from SEER in five-year age intervals through 80-84 years of age.
We
use the rates from the 11 registries, 1992-1999. 1999 is the most recent data available. So how do we use this to calculate the
expected value? Well, take each year or
fraction thereof that a person in the trial taking adalimumab is followed at a
given year of age for diagnosis of cancer.
Call that y.
Let
r be the annual incidence rate of cancer at that age in the general population
for a person of the same race and same sex.
Then the contribution to the expected number of cancers for that year of
age and that person is y x r. You get a
similar contribution for every year of age that that patient is followed. Sum those up to get the contribution for that
person.
This
is best illustrated by an example. So
let's consider a white man with first adalimumab injection at age 79 years, 3
months, who is then followed for 2.5 years.
Okay. So that's three-quarters of
a year that he is followed at age 79.
We
get the lymphoma rate for 75 to 79 years of age from SEER for white men. Multiply that by 0.75, the length of time he
was followed at age 79, and this is his contribution at age 79.
Now
he was also followed for an entire year age 80 and three-quarters of a year at
age 81. So we get the SEER rate again
for white men in the age group 80-84 years of age. Multiply that by the length of time he is
followed in that age category, and here you have the contribution of this man
to the overall expected value from ages 80 and 81, and his total contribution
then to the expected number of lymphomas in all of the patients is the
contribution at age 79 plus the contribution at ages 80 and 81. It is 319 per 100,000 or 0.0032. This is his contribution to the total
expected value.
What
this represents is the probability that he would have developed a lymphoma in
the 2.5 years he was followed using SEER rates for white men.
Now
you get a similar contribution for each of the 2,468 patients who received
adalimumab, and the overall expected value is just the sum of all these 2,468
expected contributions. Then the SIR is
calculated by dividing the observed number of lymphomas to this overall
expected number of lymphomas.
This
is the result. You have seen this
before. For lymphoma there were 10
observed lymphomas. The total expected
was 1.8. Divide 10 by 1.8, and you get
the SIR of 5.5.
Now
I think it is noteworthy that both NHL and Hodgkin's disease were elevated,
even though this is based on small numbers.
This was actually seen for all three of the drugs under consideration
today. There is an increase in both NHL
and Hodgkin's disease, and this is exactly what you would expect form a
rheumatoid arthritis population.
All
of the large population based cohort studies have shown that both NHL and
Hodgkin's disease are at increased risk in rheumatoid arthritis patients. In fact, most have shown a slightly larger
relative risk for Hodgkin's disease than for NHL.
All
right. The committee has been asked to
make recommendations -- Well, I want to say one more thing about that, because
that contrasts with what is seen in severely immunosuppressed patients, the
implant patients.
In
those patients, only NHL is elevated.
There is no evidence that Hodgkin's disease is elevated by severe
immunosuppression.
All
right. The committee has been asked to
make recommendations about the use of SIRs to evaluate cancer risks in clinical
trials and also with regard to labeling.
So I have just a few cautionary comments.
The
calculation of an SIR assumes that the cancer risk in the cancer registry
population is the same as the cancer risk in the cohort that you are
following. This is -- Well, this is
never strictly true for any application in epidemiology of SIRs, and that is
true also of clinical trials, and for at least two reasons in the adalimumab
trials, and in general, one related to geography and one related to calendar
period.
Sixty-two
percent of the patients in the adalimumab trials were from the United States or
Canada. Now, obviously, there is no
problem in using SEER for them. Canada
has very similar lymphoma rates as the United States.
The
other 32 percent were from Western Europe, several countries, and from
Australia. Now there are no good, large
cancer registries in those countries in Europe or in Australia. So we used the SEER rates for all of the
people, including those from Europe and Australia.
What
can be said, if you go to the World Health Organization, either their website
or their CD-ROM, and look at a map, they have global maps now for incidence and
mortality for lymphoma, and all of the countries represented in the adalimumab
trials were in the highest category of lymphoma risk.
So
it is probably not too unreasonable to use SEER for all of the patients in
these trials, but it is an assumption.
The
second issue has to do with calendar period, and this is always going to be an
issue in using SIRs in these clinical trials, because the clinical trial
follow-up is very recent years, and there is always a delay in these cancer
registries when you can actually analyze the data.
We
used the data up through 1999 to analyze these trials. Most of the follow-up was after 1999. Now this is unlikely to be a serious problem,
because it is very rare to see sharp increases or decreases in cancer incidence
in a two or three-year period, and that is generally what the lag is between
when these registries report their data.
A
second cautionary note is that the follow-up, obviously, in the clinical trials
has to be at least to the standard of the cancer registry, and for SEER that is
98 percent. So if the follow-up in the
trials has less than 98 percent ascertainment of cancers, then you are going to
get an underestimate of the risk in the trials.
A
third point: Even if you have totally
appropriate registry and you have complete ascertainment of cancer, there is
still going to be some bias in these SIRs.
That is because cancers in the general population are diagnosed as a
result of usual medical practice in the community, and the patients in the
clinical trials get much more medical surveillance.
So
it is virtually certain that in some of these patients you are diagnosing
cancers during the clinical trial period that, if they had not been in the
trial, would not have been diagnosed until after the follow-up period ends.
So
there's telescoping of a few cases from beyond the end of the follow-up into
the trial period is going to lead to an increase in the SIRs, but I don't think
this is so serious as to invalidate the use of SIRs for this purpose. It does argue strongly, I think, to exclude in situ cancers from such
considerations.
The
last point relates to labeling. I think
the most serious issue with regard to the use of SIRs in labeling has to do
with how you convey the uncertainty in the SIRs. For example, all three of the drugs under
consideration had elevated SIRs from lymphoma.
They had wide confidence intervals.
There
is clearly no significant difference between the SIRs. So how do you convey the information of these
SIRs in the labeling? My personal
opinion is confidence intervals are not the way to go.
Most
statisticians can't explain confidence intervals. So I don't know what a physician or a patient
is going to do with a confidence interval, but this is a question that has to
be answered, I think, and it is more serious in the current situation because
of the inherently increased risk of lymphoma in these patients.
The
differences you see in SIRs may simply reflect differences in the severity of
rheumatoid arthritis in the patients that were included in the different
trials.
CHAIRMAN
ABRAMSON: We have a few moments for --
Yes, of course. Sorry.
DR.
LEFKOWITH: I'll be quite brief. I think we would like to propose some
labeling considerations for you to contemplate during your deliberations.
I
think it is particularly appropriate to review this example with another
therapeutic class of drugs where a rate for serious adverse event was estimated
either at 0.02 or 0.04 events per hundred patient years from post-marketing
surveillance, but 100 times that rate was derived from clinical trials.
The
question is rhetoric. In a way, you are
in fact processing or measuring exactly the same event. What differs here is the context, and context
is important. So to summarize very
briefly, we would like to highlight -- we would like to propose these labeling
recommendations.
We
believe that information on prevention and screening should be highlighted,
because regardless how infrequent a serious event is, if a physician can do
something preemptively to screen those patients and to prevent that from
occurring, that is serving the physician community as well as patients.
We
believe that information on vigilance should be harmonized, because vigilance
is important in terms of informing the practitioner to intervene on a timely
basis. This will prevent morbidity and
mortality.
Again
rates should be described with appropriate context. Patient characteristics need to be
described. The nature of the study is
important, and I think it is appropriate to add a caveat regarding the
limitations on comparability.
SIRs
are useful for describing cancer risks with the caveats that Dr. Tarone added,
provided that you use an appropriate normative database and an appropriate
study vehicle for deriving the number of observed cancers.
Finally,
we would offer this last consideration for you to contemplate, whether absolute
risk may be more appropriate than relative risk, because these are, in essence,
relatively rare serious adverse events, and relativeness may overestimate the
probability and lead physicians and patients into drawing the wrong
conclusions.
Thank
you very much for that last comment. We
would be willing to entertain questions of clarification.
CHAIRMAN
ABRAMSON: Tom and perhaps the other
speakers can come to the podium.
Questions from the panel? Dr.
Jaffe.
DR.
JAFFE: It seems that the increased
incidence in TB but not other opportunistic infections must be telling us
something about the effect of the drug on the immune system and perhaps suggest
that macrophage function may be targeted more directly than T Cell or B Cell
function.
What
studies have been done of in vitro
immune function in these patients or in
vivo immunologic testing to try to determine the effect of the drug on
immunity?
DR.
FISCHKOFF: If I understand your question
correctly, you are first asking, one, if there is a true difference in not
seeing other opportunistic infections and, number two, what tests have been
done in terms of looking at that.
Let
me start with the second question first.
What this slide is showing is a portion of some of the studies that we
have done using flow cytometric techniques, which was a substudy of the DE009
study, specifically the United States study in patients receiving concomitant
methotrexate.
What
is shown here is that, looking at CD-56 and K-cells and also CD-14 cells, there
doesn't appear to be any dropoff or depletion in either of these cell
populations, and the end time point is six months.
Regarding
the other point, there were, and are described in the label, a number of other
opportunistic infections. So that, in
fact, we have seen a number of other infections. Specifically, we have seen two cases of
aspergillus, one of nocardia, and three of histoplasma.
So,
in fact, it is something that physicians do need to be alert to as well.
DR.
JAFFE: But not viral infections? I mean, what component of the immune system
do you think is being affected? Even
though there is not a decrease in macrophages, is there an effect on macrophage
function or macrophage chilling?
DR.
FISCHKOFF: I would hate to go beyond
what it is that we have actually studied.
In that one substudy, there were a number of other cell sets that were
looked at and also some functional studies, including some functional studies
regarding neutrophils, but that is the limit to which we have studied, and I
would hate to speculate beyond what we have done.
CHAIRMAN
ABRAMSON: Dr. Blayney?
DR.
BLAYNEY: A couple of things, both in
your slide and Dr. Liang's slide also.
There were no lung cancers seen.
Could you comment on that?
DR.
FISCHKOFF: Your question is?
DR.
BLAYNEY: Does your drug protect against
lung cancer?
DR.
FISCHKOFF: Well, you know, we did have
one case of lung cancer, and we did request that we get an indication, but they
asked us to do another study.
DR.
BLAYNEY: Also lymphoma is increasing in
the general population. Furthermore, in
the other iatrogenic immune suppression settings of transplantation and also in
HIV immune suppression, one sees lymphoma, but one also sees Kaposi's sarcoma
and melanoma, to some extent, in the transplant iatrogenic immune suppression.
You
didn't see that here. Could you comment
on that?
DR.
FISCHKOFF: Well, let me show you first
the data that we have on melanoma. Can I
have the original slide that had the rates of the various cancers, the one we
just saw?
As
you can see, we did have three melanomas.
The confidence interval includes one, although any conclusions are being
driven here by a very small number of cases.
There were no cases of Kaposi's sarcoma.
DR.
BLAYNEY: Thank you.
CHAIRMAN
ABRAMSON: Dr. Elashoff.
DR.
ELASHOFF: Yes. This question is for Dr. Tarone. How stable are these estimate of annual
incidence rates when you have broken down by age, sex, race and geographic
region? And also do the confidence
intervals that you create for the estimated SIRs reflect what is known about
variability for those rates?
DR.
TARONE: The answer to the second
question is no. They are the usual
confidence intervals calculated using exact Poisson methods, and all of the
standard methods assume that the underlying incidence rates are essentially
parameters that are known.
With
regard to the first question, well, even for our blacks and Asians, we
accumulated all of the data from 1992 to 1999.
So they are likely to be very stable, even for five-year age
groups. You mentioned geography. Obviously, we can't -- That was one of the
problems. I mean, we had to use the
entire SEER database. We didn't try to
stratify it by the state of location of the patient in the trial. It was just using nationwide rates.
CHAIRMAN
ABRAMSON: I have one final question for
this round. Dr. Gibofsky.
DR.
GIBOFSKY: Steve, is there any
correlation between either the finding of immunogenicity to adalimumab and the
occurrence of infection or malignancy, particularly lymphoma? Is there any greater or lesser incidence in
the population to develop antibodies than those who do not?
DR.
FISCHKOFF: So your question was, was
there a correlation with any important safety parameter and the incidence of
immunogenicity?
DR.
GIBOFSKY: Right, with particular
reference to either infection, malignancy or lymphoma.
DR.
FISCHKOFF: This is data from study
DE011, which is the study where patients were receiving adalimumab as
monotherapy, and overall there were 12 percent of patients that had detectable
at some point along the way, and they had multiple -- they had multiple looks to
see if there was an antibody.
As
can be seen with respect to adverse events, fatal adverse events, serious
adverse events, withdrawals or at least possibly drug related adverse events,
there is no difference between the patients who have an antibody at some point
in their course or those who never have one at any point in their course.
CHAIRMAN
ABRAMSON: Thank you. We will have time for questions when we come
back in the afternoon discussion. Thank
you very much.
We
will move on now to the Amgen presentation, Dr. Burge.
DR.
BURGE: Good morning, members of the
committee, the FDA, ladies and gentlemen.
It's a pleasure to be here today to provide a safety review of
etanercept which, as all of you are aware, has become well established as a
significant therapy for patients with rheumatoid arthritis, juvenile rheumatoid
arthritis, and now psoriatic arthritis.
The
efficacy and safety of etanercept has been reviewed before this committee on a
number of occasions: The initial review
associated with licensure in 1998, the review associated with label extension
in 2000, and then the TNF safety review in 2001.
We
welcome this opportunity to engage the committee today, and have been asked by
the FDA to focus our attention on safety observations relevant to lymphoma and
heart failure. We will begin by
describing some of the unique characteristics of etanercept, aspects of the
etanercept pharmacovigilance program. We
will then share some general observations from the extensive experience accrued
with etanercept.
We
have asked Dr. Alan Silman to then provide some perspective on the epidemiology
of lymphoma in rheumatoid arthritis patients, and we will then review our data
regarding lymphoma and heart failure and conclude by reviewing our ongoing
pharmacovigilance program.
Recognize
that etanercept was originally cloned and engineered by Immunex in 1990, and
Immunex was acquired by Amgen in 2002.
To avoid confusion, I will refer to Immunex and Amgen collectively as
Amgen for the remainder of the presentation.
Several
consultants have kindly consented to join us today: Dr. Jeffrey Borer from Cornell University
Medical Center; Dr. Mary Crow from the Hospital for Special Surgery in New
York; Dr. Annette Langer-Gould from Stanford University; Dr. Alan Silman from
the University of Manchester in the United Kingdom; and Dr. Julie Vose from the
University of Nebraska Medical Center.
Though
etanercept is in the TNF antagonist class, it is distinct as the only soluble
TNF receptor utilizing receptor binding specificity. The human protein has low immunogenicity, and
no neutralizing anti-etanercept antibodies have been detected.
Etanercept
does not active compliment nor does it initiate compliment mediated cell
lysis. The dosing schedule and
pharmacokinetic profile of etanercept results in a relatively smooth
concentration curve throughout the treatment period.
As
etanercept may be administered alone or in combination with methotrexate, it is
important to note that coadministration with methotrexate does not modify
etanercept pharmacokinetics.
We
believe that these product-specific differences in structure, function and
pharmacokinetics are relevant to etanercept's efficacy and safety
profiles. Although the focus of today's
discussion is on safety issues, in order to appropriately assess etanercept's
benefit risk profile, it is important to appreciate the efficacy of etanercept.
The
clinical improvement is rapid, substantial and sustained for up to six years in
clinical trials, and frequently permits tapering or discontinuation of
concomitant corticosteroids and methotrexate, each of which can be
independently associated with safety issues.
In
multiple clinical settings,including early rheumatoid arthritis, patients with
more advanced disease, patients treated with Enbrel as monotherapy, or in
combination with methotrexate, patients receiving etanercept consistently
receive ACR20 responses in the 70 percent range. This level of benefit has also been observed
in patients with JRA and psoriatic arthritis.
The
P-75 TNF receptor was cloned in 1990.
Etanercept was first developed and administered to RA patients in
1993. It was initially approved for
commercialization in 1998 for the reduction of signs and symptoms of rheumatoid
arthritis as used as monotherapy or in combination with methotrexate.
In
1999 etanercept was additionally approved for the treatment of children with
juvenile rheumatoid arthritis, and in June of 2000 Enbrel was approved as a
first line disease modifying therapy for rheumatoid arthritis and for an
inhibition of radiographic progression.
In
August of 2001 we provided a review of etanercept to this committee, and then
in 2002 etanercept became the first disease modifying therapeutic approved for
the treatment of psoriatic arthritis.
We
have long been committed to providing meaningful information regarding the
safety of etanercept to patients and prescribers. Even prior to product approval, Amgen and
Wyeth jointly made a substantial commitment to the development of a comprehensive
pharmacovigilance program.
During
the four years since product approval, this program has been further expanded
and includes multiple elements, as outlined here. Multiple long-term, open-label clinical
trials remain ongoing in North America and in Europe with over 1600 patients
entered, some of whom have now been observed for over six years.
Studies
of patients with comorbidities, patients on combination therapies have also
been initiated to further explore the safety profile of etanercept. Observational studies have been initiated in
other special populations, such as children with juvenile rheumatoid arthritis.
The
RADIUS program is now nearing its goal of enrolling 10,000 RA patients. This five-year program will permit monitoring
of the interaction between therapies, comorbidities, clinical status, and
safety. Several national registries of
also been implemented in Germany, Sweden, and the United Kingdom.
As
the background epidemiology for adverse events in patients with rheumatic
diseases is often not well characterized, we have sponsored several
epidemiologic studies, including a project with Ingenix UnitedHealthcare, a
database with approximately 50,000 rheumatic disease patients to establish the
background rates of adverse events in the RA, psoriatic arthritis, and
ankylosing spondylitis populations.
Surveillance
of adverse events has also been ongoing since product approval in November
1998. Special programs have been in
place, such as the Enliven and Enrollment programs. Enliven is a patient support system, and the
Enrollment program was in place to help facilitate drug distribution during the
previous period of limited supply.
Over
1.2 million phone contacts with the 150,000 patients who have received
etanercept therapy have facilitated adverse event reporting. Eighty-eight percent of all reports have been
initiated by patients, and follow-up of these patient reports with health care
providers accounts for over half of the health care provider reports. We believe that the increased interactions
with patients improves safety surveillance.
At
the time of initial approval, etanercept filled a significant unmet medical
need for patients with RA. Recognizing
that the experience at the time of approval was limited, we initiated a
significant number of additional clinical programs, some of which serve to
satisfy post-approval commitments.
In
August 2001 we met again with this committee and had the opportunity to present
a safety update which reflected the greatly expanded experience with that
representative over 111,000 patients. We
are able to present here today our experience based on over 8,000 patient years
of clinical trial experience in rheumatoid arthritis and psoriatic arthritis and
over 230,000 patient years of practice experience.
This
includes over 1,000 patients in their fifth year of therapy and over 390
patients in their sixth year of therapy.
Serious
adverse events, as defined by ICH, are carefully reported and evaluated. As you can see in this slide, whether in
early RA or more advanced disease, the rates of serious adverse events are
similar between control populations and etanercept treated patients. Furthermore, when we observe over time, the
rate of serious adverse events does not increase.
Serious
infections, defined as those associated with hospitalization or IV antibiotics,
have also been carefully monitored in clinical trials. Again, the rates of serious infection in the
control groups are similar to that seen in the etanercept group in early disease
or in more advanced disease. Again, the
rates do not increase with prolonged therapy with up to six years.
I
would like to focus our attention on a general overview of malignancies before
discussing lymphoma in detail.
When
evaluating the incidence of malignancies in the clinical experience, we also
have utilized the national Cancer Institute database, called Surveillance,
Epidemiology, and End Results or SEER database.
This
database collects population based information from multiple regions representing
14 percent of the United States population, and provides data regarding
incidence, prevalence and mortality of various malignancies.
Utilizing
age, gender, and race-specific rates for the SEER database, one can calculate
the expected number of cases in the general population relative to the trial
cohort. The expected rate can then be
used as a denominator in calculating the standardized incidence ratio or SIR.
This
table represents data regarding malignancies observed in etanercept clinical
trials. One can see that the control
group had five malignancies observed with 3.57 expected and an SIR of
1.40. In the etanercept group there were
11 with 8.80 expected with an SIR of 1.25.
In the entire etanercept experience, we see that there were 55 observed,
56.2 expected, and an SIR of 0.98.
The
rate of malignancies shown on this slide is a rate or events per 100
patient-years of observation. Once
again, the rate is similar between the control and the etanercept groups, and
there is no increase over time.
Now
we would like to have a brief discussion about the epidemiology of lymphoma in
rheumatoid arthritis. For this
presentation I would like to introduce Dr. Alan Silman, rheumatologist and
epidemiologist from the Medical Research Council of the United Kingdom, who is
currently the lead investigator for the United Kingdom National RA Registry.
Dr.
Silman is Professor at the University of Manchester and will share some of his
thoughts on the epidemiology of lymphoma in patients with RA. Dr. Silman.
DR.
SILMAN: Thank you. Much of what I am going to say today, I
guess, has already been mentioned. But
considering an estimate of the incidence or risk of lymphoma in etanercept
treated patients, ideally what we want to be able to do is to separate out
various components, the background population risk, the risk attributable to
rheumatoid arthritis per se, whether
there is an increased risk attributable to severe RA, and also what really
hasn't been mentioned this morning but I think is important is the increased
risk which is attributable to prior exposure in etanercept treated patients
with other immunosuppressive agents, for example, azathioprine and
methotrexate.
Also,
increasingly when one is evaluating the risk of lymphoma, or indeed any other
adverse event, in a group of patients treated with a biologic agent, we have to
take account of the fact they may have been treated with another biologic
agent.
We
have already heard outlined this morning the standardized incidence ratio being
the ratio of the observed to the expected number of cases. In fact, it has been pointed out that this
might not be the most appropriate descriptor to describe the increased risk
either the public at large or to health care providers.
I'd
just like to put forward two alternatives for you to consider. The first is what an epidemiologist might
call the absolute risk or the risk attributable in this case to etanercept
therapy. If we were able to calculate in
those patients treated with etanercept what their expected risk was based on
the fact of their disease, the severity of disease, and their other treatment,
what is the increased risk due to the fact of treatment?
Another
way of looking at the same data is to calculate the attributable risk
fraction. This says we've got an
observed risk. What proportion of that
is actually due to what we are interested in?
Now
this example might help. These are
made-up data, but in order to give some clarity to what I have previously said.
Suppose
in the etanercept treated cohort we have an observed incidence of three cases
of lymphoma per 1000 patient years of treatment. In that group we might have expected, based
on all the other factors I have outlined, an expected incidence of two per
1000. Therefore, the incidence ratio is
3 over 2, which equals 1.5.
I
suspect it might be more useful to look at the absolute risk where you are just
subtracting the expected from the observed, which allows you to say exactly for
each 1000 patient years of treatment there is an additional one case.
Alternatively,
by calculating that as a fraction of the overall risk, one can say, for
example, in this example, that given the number of lymphomas in etanercept
treated patients, if these data were real, a third of them are attributable to
the etanercept, and two-thirds are attributable to other factors.
I
think the challenge for all of us is to try and get the right numbers in order
to give these answers.
When
talking about the factors that we need to think about -- and again, many of
these have already been mentioned, the background incidence in the comparable
population, and I'll come back to that -- we do need accurate exposure data,
and I think completeness of follow-up is important.
It
is quite easy in all these studies to lose patients at follow-up, an
epidemiological construct we call right censorship, and that is important,
because if we are selectively losing, for example, the milder patients or those
individuals without problems, we may be selectively concentrating the adverse
events in those people we do follow up.
We
have already talked about the differences in the population and also aspects of
disease and treatment that might influence risk.
I
think Dr. Tarone has very nicely talked about how important it is to have a way
of ascertaining all cases and to validate all cases.
There
are some other methodological issues.
Again, many of these have been already considered. Lymphomas are rare, and risk estimates do
have wide confidence intervals, though I do share the point that it is
difficult to get over a confidence interval to even graduate students, never
mind the population.
The
issue of surveillance bias: Are early
lymphomas that we are picking early during the course of follow-up -- are they
likely to be due to the drug or due to better detection? Ideally, if we have sufficient numbers, we
could look for a dose response effect, as has been done, for example, in
relation to azathioprine? Is there
evidence of increasing risk in people, depending on the size of the dose,
duration dose, etcetera?
The
other point of crucial importance is the influence of length of follow-up. follow-up periods may not have equivalent
risk. When you talk about the risk per
1000 patient years or patient months of observation, it may be very different
if that period of observation is concentrated, for example, in the first 12 or
24 months rather than later periods.
One
of the problems is we have relatively small numbers, but as our experience
increases, we will be allowed to dissect out what are the periods of greatest
risk.
I
just want to discuss a little of the data with you on the variation in lymphoma
incidence in RA populations. I don't
believe there is any doubt that there is an increased risk in lymphoma in
patients with rheumatoid arthritis independent of the treatment they have
received, and all these studies come from the pre-biologics era.
I
think what is interesting and maybe the take-home message here is that there is
considerable variation even within the RA population. Now some of this, particularly those two high
bars at the right, might represent individuals with severer disease than in the
other bars, which are more attempt at a population derived cohort. But the message is clear. There possibly isn't one estimate of
increased risk of lymphoma in RA.
What
I have done here is to pick out the four largest population based studies and
attempted to derive a pooled estimate, as far as one can tell, in relation to
the lymphoma risk in the background RA population.
These
are studies from very different parts of the world, from Europe and from North
America. Actually, the dramatic thing --
and in epidemiological terms, believe me, it is dramatic -- the similarity in
risk are twofold with a fairly narrow band of upper and lower confidence
intervals.
I
think these data are persuasive that, if one goes to a population level, you do
find this increased risk.
I'd
just like to finish by just letting you know what is happening in Europe and in
the U.K. in particular. In the U.K. now,
physicians can only prescribe anti-TNF agents if they register them with the
National Biologics Register, which is based in my own group in Manchester.
We
are attempting to follow up both cohorts treated with etanercept as well as the
other agents compared with cohorts that could be treated, if we had the
funding, but are not, and allowing us to match for the various disease and
other treatment characteristics.
We
are also combining this effort, as I think you have already heard from both Dr.
Fischkoff and Dr. Burge, with other registries in Europe to try and get the
larger numbers. But I think, in answer
to a question you have not yet raised, my guess is the answer to this might not
come for another three of four years.
Thank
you very much. I think Dr. Burge is going to continue.
DR.
BURGE: Thank you, Dr. Silman. We would now like to discuss the available
data on lymphoma from etanercept clinical trials in the post-marketing
experience. We will review the histology
of lymphoma reports, and state the conclusions that can be drawn from this
data.
Recall
that an accurate estimation of SIR is dependent on precise ascertainment of
incident cases and the corresponding period of observation. Clinical studies provide the only opportunity
to accurately estimate the SIR for this treated population.
In
the etanercept clinical trials program, six cases of lymphoma have been
reported on study. Utilizing the SEER
database applied to a comparable cohort in the general population, one would
expect 2.59 cases, yielding an SIR of 2.31.
Note that the confidence interval includes 11, and the point estimate is
similar to the 2.2 represented by Dr. Silman.
Note
that this table here will also act as a reference in the next three slides for
further analysis.
Etanercept
has been evaluated in a broad range of populations. The vast majority of our patients, regardless
of disease duration, had moderate to severe RA with mean tender and swollen
joint counts in the high twenties. Other
than the early RA study, patients had typically failed three or more DMARDs and
had a mean disease duration of over ten years.
Evaluating
the lymphoma SIR in early and in more advanced disease, we obtained numbers
that are actually quite similar. Additionally,
time to onset is dispersed with a range of 0.4 to 4.8 years.
Three
additional lymphomas have been reported after study completion in patients
previously treated with etanercept in clinical trials. As the period of post-trial observation for
all patients is not known, an accurate denominator cannot be calculated, and we
cannot derive an accurate SIR. However,
if we consider only the patient time on study and use the expected number of
2.5, this conservative SIR is 3.47.
The
SIR calculated in the previous slides have been relative to the general
population. Using the benchmark of
2.2-fold increased risk described by Dr. Silman for the general RA population,
we multiplied the 2.59 expected cases by the 2.2 and derived an expected number
of 5.7 for the RA population. The SIR
for this analysis is 1.05.
Recognize
that patients treated with etanercept do have more severe disease than the
general RA population, which is known to
confer greater risk and is not included in this analysis.
Lymphomas
have been described in post-marketing reports in patients who have received
etanercept therapy. The reporting rate
is 0.3 cases per 1000 patient years. The
background incidence in the general population is 0.3 per 1000 patient years,
and utilizing the adjustment of 2.2 would yield an incidence for the RA
population of 0.66 per thousand patient years.
As
would be expected in a predominantly RA population, most of the reports are
from women. The mean age is 61, and the
majority of patients were previously treated with methotrexate.
We
have carefully tracked these reports since commercialization. Shown here are the rate of reports by report
date, in blue, and by diagnosis state, in -- excuse me, report date, in yellow,
and diagnosis date, in blue.
As
one can see, the reporting rate for lymphoma presented here in six-month
intervals is stable over the four years of commercial experience.
We
have evaluated the distribution of subtypes of lymphoma in the clinical trials
and post-marketing experience. As can be
seen in this slide, the distribution, 14 percent of Hodgkin's and 86 percent
non-Hodgkin's, is nearly identical to that expected in the general population
utilizing rates in the SEER database.
We
additionally obtain, whenever possible, pathology reports on cases of lymphoma
and have them reviewed by an oncologist or a hematopathologist for
classification into histologic subtypes.
Histopathology was obtained for almost 70 percent of all these reports.
The
distribution of the NHL subtypes is
compared here to the distribution reported in the literature for a
rheumatoid arthritis population and a non-RA control group. The distribution of histologic subtypes is
similar in all three groups.
Immunosuppression
such as that seen following organ transplantation is associated commonly with
an increase in the proportion of diffuse large B Cell lymphomas, and this
pattern is not seen with etanercept therapy, as shown on the first line of this
slide.
In
conclusion, lymphoma reports with etanercept are rare. A comprehensive pharmacovigilance program has
been in place for four and a half years, and the rate of lymphomas observed in
clinical trials is consistent with the expected rate for RA patients with an
SIR of 2.3.
Our
post-marketing experience is compatible with the clinical experience, and the
distribution of histologic subtypes is as expected. With six years of sustained therapy, we see
no evidence of an increase in lymphoma incidence.
Amgen
supports proactive communication to health care providers and has initiated
processes to assure timely dissemination of this information. We, therefore, in the latter part of 1002
submitted a proposal to the FDA to represent the lymphoma experience in the
adverse events section of the etanercept package insert.
The
purpose of this proposal was twofold:
First, to inform physicians that the background incidence of lymphoma in
RA was increased; and, two, that the observed incidence of lymphoproliferative
disorders from clinical trials and post-marketing reporting rate are similar to
that expected.
We
additionally have presented this data at scientific meetings for
rheumatologists at ACR and at EULAR, and we believe that the programs we have
in place, long term clinical trials, observational studies, further
characterization of epidemiology, and continued safety surveillance are an
important part of our commitment to patients.
In
2002 the product label was updated from information from the etanercept heart
failure program, which was designed to test the hypothesis that etanercept was
effective in treating chronic heart failure.
We would like to share some of the observations from this study.
The
etanercept CHF program consisted of over 2000 patients in two studies. The global trial called RECOVER included
three treatment arms, as outlined by Dr. Unger earlier, a placebo group,
Enbrel-25 once a week, and twice a week.
I apologize. I'm describing the
lower part of the slide. And the
RENAISSANCE trial included three treatment arms also, the placebo, 25 twice a
week, and 25 three times a week.
The
analysis of the combined studies was called RENEWAL. The program had in place predefined interim
analyses for safety and efficacy. One of
these analyses, a futility analysis, specified that studies were to be
discontinued if meaningful clinical benefit was not likely to e
demonstrated. In March of 2001, the
futility endpoint was met, and the studies were stopped.
The
primary efficacy endpoint of RENEWAL, the analysis of combined studies, was the
time to all-cause mortality and CHF hospitalization. This morbidity and mortality endpoint was
also evaluated in the individual studies, but was not the primary endpoint.
As
you can see here, each of the treatment groups is shown with the relative risk
to placebo within the study. Note that
the confidence intervals of all analyses include 1, and that in the RENAISSANCE
study, the relative risks trend toward worse heart failure outcomes in patients
treated with etanercept.
These
observations are not duplicated in the RECOVER study, and the combined
analysis, RENEWAL, had a relative risk of 1.10.
A
number of characteristics that were known to have significant impact on heart
failure outcomes were prospectively identified as covariates relevant to the
interpretation of these trial findings.
In
the RENAISSANCE study, randomization of patients resulted in imbalances of some
of these characteristics in favor of the placebo group. For example, the percentage of patients with
a history of atrial fibrillation or atrial flutter is 29 percent in the placebo
group and 36 percent in each of the etanercept groups.
The
left side of this slide represents the data previously shown. On the right side of the slide is the
relative risk after adjustment using Cox proportional hazards regression for
the predictive and imbalance covariates.
The trends seen in the RENAISSANCE study have diminished, and the
combined analysis results in a relative risk of 1.01.
This
slide represents a secondary endpoint of time to all cause mortality. The findings of this endpoint are similar to
those of the primary endpoint shown previously.
There was a trend in worse outcomes in the RENAISSANCE study that was not
duplicated in RECOVER. Again, after
accounting for covariates, the trends do diminish, and the relative risk of the
combined analysis is 0.96.
In
conjunction with review of the data from patients with underlying heart
failure, we also analyzed heart failure occurrence in rheumatic disease
studies, patients who were not known to have underlying heart disease.
The
number of subjects developing new onset heart failure was similar, and was the
same in the etanercept and control arms of the controlled trials. As much of our experience is from open-label
observations where no comparator is available, we have used benchmarks from the
literature to calculate the expected number of cases.
The
number of cases of new onset CHF treated with etanercept in rheumatic disease
trials was seven, compared to the 15.2 expected. So the rate of new onset CHF is not increased
in rheumatic disease trials.
Despite
no clear evidence of deleterious effect of etanercept in heart failure, it was
important to communicate these findings to health care providers, particularly
rheumatologists. On that basis, in May
of 2002 we added a precaution in the product label. Additionally, the data from the heart failure
trials was presented at scientific meetings for cardiologists and
rheumatologists.
In
conclusion, two large heart failure studies were discontinued due to lack of
efficacy and, although one of the two studies showed a trend toward worse heart
failure outcomes, the second trial did not.
Overall, there is no clear treatment effect of etanercept in heart failure
patients.
Additionally,
there is no evidence from rheumatic disease trials that etanercept increases
risk for CHF. However, we chose to
inform prescribers this important information through labeling and at
scientific meetings.
We
have built a foundation of extensive, long term safety experience with
etanercept. This experience encompasses
the clinical trials previously discussed here in this presentation,
complemented by observational and long term studies, epidemiologic studies, and
ongoing safety surveillance. Amgen is
committed to proactive communication.
This
table summarizes the initiatives that are being conducted by Amgen and
Wyeth. We anticipate that these programs
going forward will provide further insights into the safety issues discussed
today.
The
long term clinical trials where we have already accrued five years of
experience will be conducted for at least ten years. Additionally, the ongoing RADIUS program will
prospectively observe 10,000 RA patients for five years in the clinical
practice setting.
Furthermore,
a JRA registry has been established in the U.S., and national RA registries
have been implemented in Germany, Sweden, and the United Kingdom.
This
comprehensive program will advance the understanding of etanercept and
underscores Amgen's and Wyeth's commitment to patient safety.
Three-year
safety and efficacy data from our long term trials have been included in our
product label, and we have submitted to the FDA four-year data. We plan to submit data regarding five years
of etanercept experience to the FDA this summer. These data have been included in these
presentations.
Although
we have nearly fulfilled our post-marketing commitment to the FDA, we will
continue to follow these patients for an additional five years.
In
summary, the soluble receptor etanercept has unique structure, mechanism of
action, and pharmacokinetic that, we believe, make etanercept a unique
therapeutic. Etanercept has an
established track record with over nine years of experience in treating
rheumatic disease patients and four years of clinical practice experience.
This
extensive experience, along with a robust pharmacovigilance program, has
allowed us to characterize the etanercept safety profile. With its highly favorable benefit/risk
profile, etanercept remains a very important contribution in the therapy of
patients with rheumatic diseases. Thank
you.
CHAIRMAN
ABRAMSON: Thank you very much. Are there questions? Dr. Makuch?
DR.
MAKUCH: Just a few questions. One relates to the futility. I mean, it really seemed like a very
one-sided hypothesis, namely -- I think I got it right -- is that, if
meaningful clinical benefits could not be achieved, then you would stop the
study.
On
the other hand, if one is looking at a safety concern, that seems to be not the
proper hypothesis to look at. You would
like to know whether there is clinical benefit or perhaps clinical harm.
So
it then gets to the second comment, that RENAISSANCE was your longer study, and
then you went on to indicate that the RECOVER study did not replicate in some
sense the RENAISSANCE results.
I
guess I'm not surprised that that is the case, because the RECOVER study had a
very much shorter median follow-up period.
I think we heard earlier that it was 5.7 months compared to over a year
for the RENAISSANCE study.
The
final comment then is with respect to the covariates, you show the analyses
again trying to make any marginal trends go away, that once you include
covariates then, even for RENAISSANCE, the results really were very null.
I
think we are all aware of the problems that one has when throwing in lots of
covariates into a model. So my general
comment is how was it determined that these studies were stopped early and
that, it appears to me -- I have a little discomfort with respect to concluding
that, one, the RECOVER study did not replicate the RENAISSANCE -- I'm not
surprised -- and two, with respect to the one-sided hypothesis seemed to be
used for the futility?
DR.
BURGE: There were several pre-defined
analyses that the data monitoring committee were charged with evaluating on an
ongoing basis when they had these data monitoring committee meetings, and there
were discussions about, or rules for stopping for efficacy as well as stopping
for safety.
The
efficacy rule was that the study would be discontinued if there was no evidence
-- if it was not likely that there would be the ability to show at least a ten
percent benefit with etanercept, and it was on that basis that the study was
discontinued.
The
committee very specifically, when they did their review, mentioned that it did
not meet their threshold for discontinuing the study on safety grounds.
CHAIRMAN
ABRAMSON: Dr. Elashoff.
DR.
ELASHOFF: Yes. This question is for Dr. Silman. The attributable risk fraction as defined on
the first slide and as done in the example on the second slide do not
agree. So perhaps you could say which is
the correct formula. If it's the first
one, then it's just the SIR minus 1.
DR.
SILMAN: Sorry. Can I have the slide back on? I sit possible to have the slide back on?
DR.
ELASHOFF: So is this the correct
formula?
DR.
SILMAN: Just let me check. It's the observed -- Sorry, it's observed
minus expected. So that -- It's observed
minus expected over the observed.
DR.
ELASHOFF: So this formula is incorrect
then on this one?
DR.
SILMAN; Yes. Sorry, I apologize for that. Thank you.
Yes.
CHAIRMAN
ABRAMSON: Dr. Blayney.
DR.
BLAYNEY: In the -- Directed to the
congestive heart failure experience with etanercept, you have about 2000
patients that you followed for half a year to a year. What was the lymphoma risk observed in those
people, and the tubercular infection rate observed in -- tuberculosis infection
rate observed in those people who are not presumably previously exposed to
DMARDs or other kinds of immunosuppressives?
DR.
BURGE: The first part of your question
was referring to -- I'm sorry. There's
so many parts to that, I lost track.
DR.
BLAYNEY: The adverse effects in a
congestive heart failure trial presumably includes secondary --
DR.
BURGE: Lymphoma, infections, TB,
yes. Lymphoma, if you calculate an
expected rate of lymphoma in the congestive heart program, the entirety of that
would be age, sex, match adjustments.
The expected is 0.7 lymphomas.
There was one lymphoma observed in that experience.
As
far as all serious infections, it
actually was actually even across all treatment groups actually in both
trials.
There
was one case of tuberculosis in the European trial.
DR.
BLAYNEY: Thank you.
CHAIRMAN
ABRAMSON: Yes, Dr. Manzi.
DR.
MANZI: I just have two fairly direct
questions. The first is: In relationship to looking at congestive
heart failure in the RA trials, I think that's very different than in the
trials where you are specifically entering people with obviously active
congestive heart failure. My guess is
that there may have been some selection or exclusion of patients with either
active or comorbid conditions in the RA trials, so that the population may be
very different than how it will be used post-marketing. Is that --
DR.
BURGE: Yes. The clinical trials had exclusion for severe
uncompensated heart failure, but having any heart failure was not
excluded. We primarily looked at the
rheumatoid arthritis and the other rheumatic disease trials to look for new
onset heart failure, because certainly the database we have from the
2000-patient clinical program in heart failure is much more meaningful to
evaluate exacerbations of heart failure than any experiences we have in this small
number of cases in the rheumatic disease trials.
DR.
MANZI: And my last question is for Dr.
Silman. That is: When you give us the SIR for RA patients in
general with this twofold increased risk, I am assuming that is not independent
of prior immunosuppressive exposure.
DR.
SILMAN: That's a very good
question. I mean, the data that do exist
actually don't give us that information.
Interestingly, the study that showed the highest risk, which was the
smallest study from the United Kingdom, actually was independent of
immunosuppressive data, but the studies that I presented, the larger studies,
there are not data available.
CHAIRMAN
ABRAMSON: Dr. Burge, can I just get a
clarification of the numbers? You saw
six lymphomas during the randomized trials, and then you discussed 70
subsequent to that. Were they in your
registries and open-label extensions or were some of those MedWatch type
reports?
DR.
BURGE: The 70 was the post-marketing
experience of spontaneous and facilitated reporting.
CHAIRMAN
ABRAMSON: Separate from registries that
you had yourselves?
DR.
BURGE: It would include anything other than the clinical trials.
CHAIRMAN
ABRAMSON: Thank you very much.
The
next presentations will be by Centocor, and Dr. Boscia will make the first
presentation.
DR.
BOSCIA: Well, the good news is I promise
to only spend one sentence on SEER and one sentence on SIR. I promise.
Good
morning. My name is Dr. Jerry
Boscia. I am Vice President of
Clinical Research & Development at
Centocor. On behalf of Centocor and
Johnson & Johnson, I would like to express appreciation for this
opportunity to present information on REMICADE, or infliximab.
I
would particularly like to express appreciation to Dr. Jeffrey Siegel at the
FDA who we occasionally drive crazy. But
of course, he never drives us crazy.
REMICADE
is a monoclonal antibody that is specifically directed against human tumor
necrosis factor alpha. After this brief
introduction, I will be providing some background information with regard to
REMICADE's safety profile.
Specifically,
I will cover the following topics:
Lymphoma; other malignancies; tuberculosis; opportunistic infections;
and heart failure. I will spend the
majority of my time on lymphoma, for obvious reasons. If you have questions on safety topics not
addressed by me, we will be happy to answer them.
Dr.
Tom Schaible will then summarize Centocor's ongoing and planned studies and
registries for the continuing characterization of REMICADE's safety
profile. He will briefly discuss
REMICADE's efficacy and have some concluding remarks.
We
have a short time to present our information, but in case anyone has additional
questions, we have with us today several consultants who can help answer any
questions. They are: Dr. Roger Cohen, a hematologist/oncologist
from the Fox Chase Cancer Center; Dr. Susan Fisher, an oncologic epidemiologist
from the University of Rochester; Dr. Stephen Hanauer, a gastroenterologist
from the University of Chicago; Dr. Milton Packer, a cardiologist from Columbia
University; Dr. Paul Stang, an epidemiologist from Galt Associates; Dr. William
ST. Clair, a rheumatologist from Duke University; and finally, Dr. Frederick
Wolfe, a rheumatologist from the Arthritis Research Center Foundation.
I
would like to spend just a few minutes reminding everyone of the burden of
disease with regard to rheumatoid arthritis and Crohn's disease. As an infectious diseases physician -- that's
my training -- I sometimes have to remind myself. So for the non-rheumatologists and
non-gastroenterologists in the room, I thought I would just take a few minutes
to do this.
Upwards
of 90 percent of patients with aggressive rheumatoid arthritis develop
significant disability within 20 years of diagnosis. Furthermore, the life expectancy of patients
with rheumatoid arthritis is reduced compared with the general population.
Crohn's
disease is a debilitating disease, mostly affecting young adults. In about half of patients it has a
detrimental impact on patients' ability to work and/or their productivity at
work. As many as 90 percent of patients
with Crohn's disease require surgical intervention, and most of them require
additional surgeries.
REMICADE
is indicated for patients with rheumatoid arthritis and Crohn's disease who
have had an inadequate response to conventional therapies. During Dr. Schaible's brief discussion of
efficacy towards the end of this
presentation, you will see that REMICADE fulfills previously unmet medical
needs with its profound benefit in a majority of patients.
REMICADE
as a potent biologic also has safety issues.
Centocor has been, and continues to be, diligent in characterizing
REMICADE's safety profile. We presented
a safety assessment of REMICADE to this committee in August 2001. Today we will update the committee with new
data from our clinical trials, large registries, and spontaneous adverse event
reports.
Centocor
has completed 15 clinical trials with REMICADE in patients with rheumatoid
arthritis and Crohn's disease, encompassing approximately 1700 patients treated
for almost 3500 patient years. An
additional 14 trials are ongoing in patients for a variety of diseases,
encompassing about 3100 patients treated with REMICADE.
We
estimate that, through August 2002 which was the last cutoff date for reporting
to worldwide health authorities, 365,000 patients for about 554,000 patient
years of exposure had been treated commercially with REMICADE worldwide. This number of patients treated is now well
over 400,000.
I
will now review our data examining the risk of lymphoma and other malignancies
associated with REMICADE treatment. As
reviewed in the briefing document, an increased risk of lymphoma is associated
with having rheumatoid arthritis or Crohn's disease.
Comparisons
of lymphoma risk in these populations are typically made with age, race, gender
matched, general population from the Surveillance Epidemiology and End Results
or SEER database.
Lymphomas
are more common in patients with rheumatoid arthritis compared with the general
population, as demonstrated by standardized incidence ratios or SIRs of 2 to 3,
as reported in the literature. Elevated
relative risk is associated with greater inflammatory activity, as much as a
26-fold increase, poor functional class, and involvement of both the small and
large joints.
Use
of conventional immunosuppressants such as azathioprine have also been
associated with increased risk. Although
the epidemiologic data supporting increased risk of lymphoma in Crohn's disease
is not as compelling as for rheumatoid arthritis, the preponderance of studies
suggests an association.
This
table summarizes number of patients, patient years of follow-up, observed
numbers of lymphomas, and SIRs for REMICADE clinical trials in rheumatoid
arthritis. The assessment of SIRs for
lymphoma is based on a comparison with the number of lymphomas expected in an
age, race, gender matched, general population from the SEER database.
This
is not as relevant a comparison as it would be against a population of patients
with rheumatoid arthritis or, better yet, against a rheumatoid arthritis
population with a similar level of disease activity as in the REMICADE clinical
trials.
In
contrast to our other analyses, this table also includes our recently
completely trial in patients with early rheumatoid arthritis in order to show
the differences between various rheumatoid arthritis populations.
For
all REMICADE arthritis studies combined, the SIR for REMICADE treated patients
is 6.4. We observed that no lymphomas
occurred in a methotrexate naive early rheumatoid arthritis population who
received REMICADE, compared with four lymphomas in a disease modifying
anti-rheumatic drug or DMARD resistant high disease burden population, studied
in our other rheumatoid arthritis studies.
These
findings are consistent with the epidemiologic data I presented on the last
slide. The SIRs for patients who
received placebo are all zero. However,
please note that the placebo patient years of follow-up is only 18 percent of
the REMICADE patient years of follow-up in the DMARD resistant rheumatoid
arthritis population, the group in which all four of the lymphomas occur.
Although
the SIRs are greater for the REMICADE treated patients compared with the
placebo treated patients, the 95 percent confidence intervals are wide and
overlap.
This
table summarizes the same information as the last one did for lymphomas, except
this one does it for REMICADE clinical trials in Crohn's disease, and then for
all REMICADE studies from this and the last slide combined.
For
all Crohn's disease studies, the SIR for REMICADE treated patients based on two
cases of lymphoma is 8.7. The SIR for
patients who received placebo is zero.
However, please note that the placebo patient years of follow-up is only
six percent of the REMICADE patient years of follow-up.
For
all rheumatoid arthritis and Crohn's disease studies combined, the SIR for
REMICADE treated patients is 7.0.
Although the SIR for patients who received placebo is zero, the placebo
patient years of follow-up is only 17 percent of the REMICADE patient years of
follow-up.
Once
again, the SIRs are greater for REMICADE treated patients compared with placebo
treated patients, but the 95 percent confidence intervals are wide and overlap.
For
those in the audience who wish to know the incidence of lymphomas in our
clinical trials, I present this table -- in other words, if you prefer
incidence rather than SIRs.
These
are shown for all REMICADE rheumatoid arthritis studies, all Crohn's disease
trials, and both combined. Please note
that the incidence is per 1,000 patient years of follow-up.
At
study entry, the four patients with moderately to severely active rheumatoid
arthritis who developed lymphomas had long disease duration, substantial joint
involvement, and significant elevated sedimentation rates. All of these are factors associated with
increased risk of lymphoma.
This
figure summarizes the latency in months from first infusion to diagnosis, as
shown with the yellow bars, REMICADE dose and number of infusions -- the number
of infusions are shown as orange arrows underneath the yellow bars -- and other
medications received for the four patients with rheumatoid arthritis who
developed lymphoma.
The
first three of these four cases were reviewed at our presentation to the FDA
Gastrointestinal Advisory Committee meeting in 1998 when REMICADE was approved
for Crohn's disease -- not approved; when it was recommended for approval. Sorry about that.
The
fourth case is new since that time. The
four cases had a diverse histologic profile.
One lymphoma was high grade, the grade most commonly observed in the
setting of immunosuppression. The other
three were not high grade and included an indolent lymphoma, a mantle cell
lymphoma, and a Hodgkin's lymphoma.
No
apparent relationship to REMICADE exposure was observed, with the third patient
in this figure having received only a single dose of 1 mg/kg. Patients two and four had received
azathioprine in their past, and the fourth patient started receiving etanercept
about three months prior to diagnosis of lymphoma.
This
figure summarizes the same information as the last one, except this one does it
for the two patients with Crohn's disease who developed lymphomas. The first of these two cases was also
reviewed at that 1998 FDA Gastrointestinal Advisory Committee meeting. The second case is new since that time.
These
cases also had diverse histology. One of
these lymphomas was an intermediate grade B-cell lymphoma of histology that can
occur in the setting of immunosuppression, and the other was an NK
lymphoma. Both patients received only a
single dose of REMICADE, and both were also receiving azathioprine.
Now
this could be important. Unfortunately,
we have Dr. Wolfe here with us here today.
As we reviewed in our presentation to this committee in August 2001, we
are supporting Dr. Frederick Wolfe's national data bank for rheumatic diseases
to obtain long term follow-up for safety and outcomes in patients receiving
commercially supplied REMICADE.
Dr.
Wolfe's extensive database in over 18,000 patients with rheumatoid arthritis
enables the comparison of REMICADE treated patients with patients who have not
received REMICADE. The patients in the
registry are from 908 rheumatology practices in the United States. Dr. Wolfe's group captures data twice yearly
using a mailed questionnaire.
Several
parameters are assessed, including adverse events and outcomes. There is a validation process to maximize
accuracy and reliability. The registry
retains a high retention rate of its patients with approximately an eight
percent attrition rate each year.
The
same information that I summarized earlier for the clinical trial lymphoma
cases is summarized in this and the next table for the lymphoma cases in Dr.
Wolfe's registry. Again, this uses the
SEER database to determine the expected number of cases.
This
table shows the SIRs for lymphoma patients who received no methotrexate or
anti-TNF therapy, those who received methotrexate but no anti-TNF therapy, and
those who received REMICADE and/or etanercept.
Please note that three patients received both REMICADE and etanercept
and are represented in both the REMICADE and etanercept lines.
When
evaluating the SIRs on this slide, please note that the patients receiving
anti-TNF therapy are probably at greater risk for lymphomas compared with those
not receiving anti-TNF therapy, due to greater levels of disease activity
refractory to standard treatment. So
when you look at those, 1.3, 1.5, 2.6, and 3.8, remember that.
We
also reviewed with this committee in 2001 our plan to develop the Crohn's
therapy resource evaluation and assessment tool or TREAT registry. This registry has now enrolled 5,000
patients, including both patients treated and not treated with REMICADE.
The
TREAT registry enrolled patients with Crohn's disease who were 18 years or age
or older and were willing to participate for at least five years. Patients completed a health status
questionnaire at baseline, and they do so every six months. Data collected includes adverse events and
outcomes.
Follow-up
data is now available in approximately 1100 REMICADE treated patients, and 1300
patients not treated with REMICADE. The
number of reported lymphomas is shown here.
One lymphoma has been reported in a REMICADE treated patient, and one
has been reported in a patient not exposed to REMICADE.
Spontaneous
adverse event reports of lymphoma are summarized in this slide. A total of 71 lymphomas were reported in
patients with rheumatoid arthritis, Crohn's disease, and other diseases through
August 2002, the last cutoff date for reporting to worldwide health
authorities.
When
Dr. Cote presented this information earlier -- Dr. Cote from the FDA -- he
mentioned 95 cases of lymphoma. His
cutoff, though, was December of 2002, and that explains the difference. Our numbers match his through December.
In
summary, lymphomas are common in patients with rheumatoid arthritis -- are more
common in patients with rheumatoid arthritis compared with the general
population, as demonstrated by SIRs of 2 to 3.
The risk increases with increasing severity of disease.
An
SIR of 6.4 for lymphoma was observed in REMICADE treated patients compared with
the general population from the SEER database in our clinical trials. However, the lymphomas occurred in patients
who had known risk factors for elevating lymphoma risk. These included high inflammatory activity,
high disease burden, and long term exposure to immunosuppressive agents.
An
SIR of 2.6 for lymphoma was observed in REMICADE treated patients compared with
the general population from the SEER database in Dr. Wolfe's registry. Based on all this, the rates of lymphomas may
not be greater in the REMICADE treated rheumatoid arthritis and Crohn's disease
populations compared with populations with similar levels of disease activity
who do not receive REMICADE.
Centocor
remains committed to continue to examine the potential lymphoma risk in
clinical trials, large registries and post-marketing pharmacovigilance. We look forward to the FDA Arthritis Advisory
Committee's and FDA's deliberation, assessment, and guidance on the best
approach to studying the potential risk of lymphoma with anti-TNF therapy, and
the best means to communicate to treating physicians in our prescribing
information.
We
feel current evidence is insufficient to reach conclusions on whether REMICADE
increases the risk of lymphomas.
We
will now -- I will now -- I will now briefly review our clinical trial and
spontaneous adverse event reports of non-lymphoma malignancies in rheumatoid
arthritis and Crohn's disease.
To
date, epidemiologic studies in large rheumatoid arthritis cohorts have not
demonstrated an increased risk of non-lymphoma malignancies in this disease. Longstanding Crohn's disease predisposes to
intestinal malignancies, with the risk of colon carcinoma for Crohn's colitis
thought to be similar to ulcerative colitis.
This
table summarizes the same information for non-lymphoma malignancies in REMICADE
clinical trials as I showed earlier for lymphomas. Once again, this uses the SEER database to
determine the expected number of cases.
For
all rheumatoid arthritis studies, all Crohn's disease studies, and all studies
combined, the SIRs for REMICADE treated patients approximate one. They are no greater than the SIRs for placebo
treated patients, despite the fact that the placebo patient years of follow-up
are only 6 to 18 percent of the REMICADE patient years of follow-up. Admittedly, the number of non-lymphoma
malignancies in the placebo treated patients is small.
Robby,
can you go back, please? When Dr. Liang
from the FDA presented this data, he presented it with the ASPIRE trial, and we
have that, and we can present it that way also.
The reason we chose not to include ASPIRE in this analysis is because
it's still blinded, and we didn't know which groups, of course, to put the five
malignancies that exist and have occurred in ASPIRE. We didn't know where to put them.
Dr.
Liang presented the worse case scenario, and we can also put that slide back
up, if the committee would like to see it once again.
In
our post-marketing commercial experience, 354 non-lymphoma malignancies have
been reported in patients with rheumatoid arthritis, Crohn's disease, and other
diseases through August 2002. This
includes 230 in patients with rheumatoid arthritis and 68 in patients with
Crohn's disease.
Taken
together, our clinical trial data and spontaneous adverse event reports are
insufficient to reach conclusions on whether REMICADE increases the risk of
non-lymphoma malignancies.
The
topic of tuberculosis was covered in detail with this committee in August
2001. Just prior to that meeting,
Centocor added a box warning addressing tuberculosis in our prescribing
information.
Associated
with this was the mailing of a Dear Health Care Professional letter. Also, during August and September of that
year, we implemented our tuberculosis medical risk management education
program. This involved about 7500
rheumatologists and gastroenterologists in the United States.
Our
follow-up of this program indicates that most of these physicians evaluate
patients for latent tuberculosis infection with a tuberculin skin test prior to
therapy with REMICADE.
Also,
there has been a decreased number of spontaneous reports of tuberculosis,
despite a steady increase in the number of patients, including new patients,
treated with REMICADE. Before Dr. Miles
Braun has chest pain, I should mention that we realize that part of this effect
could be due to a decrease in reporting efficiency.
This
table depicts the worldwide reports in REMICADE treated patients for a variety
of viral, bacterial, and fungal opportunistic infections reported during
post-marketing surveillance through August 2002. Potential confounding factors for the
development of opportunistic infections include the fact that patients with
rheumatoid arthritis being treated with REMICADE also received methotrexate,
since REMICADE is labeled for combination use with methotrexate.
Furthermore,
patients with rheumatoid arthritis as well as patients with Crohn's disease
typically receive other additional immunosuppressive agents, such as
corticosteroids, azathioprine, 6-mercaptopurine, and others. Often, patients are receiving two or more of
these immunosuppressants.
The
cases of histoplasmosis and coccidioidomycosis have, for the most part,
occurred in the Ohio, Mississippi River Valleys and southwest Untied States
respectively where histoplasmosis and coccidioidomycosis are endemic.
For
patients who have resided in regions where histoplasmosis and
coccidioidomycosis are endemic, the benefits and risks of REMICADE treatment
should be carefully considered before initiation of REMICADE therapy.
With
regard to all of these opportunistic infections and tuberculosis, patients
should be monitored for signs and symptoms of infection while on or after
treatment with REMICADE. The route of
administration of REMICADE fosters regular physician- patient interaction and,
therefore, very close follow-up.
Now
I would like to turn our attention to heart failure. I know you've been through this already, but
I'll be brief.
The
ATTACH trial was a randomized, placebo controlled, Phase 2 study designed to
evaluate the effect of REMICADE in patients with Class III-IV heart failure due
to systolic dysfunction. One hundred
fifty patients were randomized to receive placebo, 5 mg/kg of REMICADE or 10
mg/kg of REMICADE at zero, 2 and 6 weeks.
The
protocol specified follow-up period was 28 weeks. In addition, survival status at one year was
determined for all patients. This table
displays the number and Kaplan-Meier rates of patients who were hospitalized
for worsening heart failure at 28 weeks, and the number and rates who died through
both 28 weeks and one year.
At
28 weeks the rates of hospitalization for worsening heart failure were similar
in the placebo and 5 mg/kg groups, but increased in the 10 mg/kg group. At the same time point, mortality was
increased in the 10 mg/kg group. By one
year, there were similar death rates in the placebo and 5 mg/kg groups, with a
persistent increase in the 10 mg/kg group.
The
REMICADE prescribing information was updated by the company in march of 2002,
at which time all patients in the ATTACH trial had completed 38 weeks of
follow-up, but one-year mortality follow-up was still ongoing.
At
that time, it was decided to contraindicate REMICADE at any dose in patients
with Class III/IV heart failure.
Although no data were available in patients with Class I/II heart
failure, avoidance of REMICADE doses greater than 5 mg/kg was recommended in
these patients.
Now
that complete results on the ATTACH trial are available, including mortality
data through one year, we are discussing with Dr. Ellis Unger at the FDA the
potential for further changes to the prescribing information.
Centocor
and the FDA -- Somebody asked this question earlier, somebody on the
committee. Centocor and the FDA have
recently focused attention on new onset heart failure. That is the appearance of heart failure in
patients with no known history of heart failure.
Reports
of heart failure in clinical trials other than ATTACH have been
infrequent. This is probably due, at
least in part, to the exclusion of patients with significant underlying cardiac
disease at study start.
This
table shows that, despite the approximately 20 percent less average follow-up
in weeks for patients on placebo compared with those on REMICADE, there is no
increase in new onset heart failure in patients treated with REMICADE compared
with those on placebo.
As
of October 2002 there were 158 spontaneous post-marketing reports of heart
failure. Twenty-eight of these had no
known history of heart failure, acute precipitating event or risk factor --
none of those. However, interpretation
of these data is confounded by incomplete and, at times, conflicting
information, as well as lack of a control group.
Centocor
is presently discussing these spontaneous cases of new onset heart failure with
the FDA.
I
would now like to introduce the person who stands between you and lunch, Dr.
Tom Schaible, Vice President of Medical Affairs at Centocor, who will summarize
our plans for continuing to assess safety in clinical trials and patient
registries.
He
will briefly discuss REMICADE efficacy and have some concluding remarks. Tom.
DR.
SCHAIBLE: Thank you, Jerry, and thank
you for putting me on the spot. I
appreciate this opportunity to speak to the advisory committee as well.
In
this presentation I would like to review with the committee our continuing
commitment to obtaining long term prospective safety information in patients
receiving REMICADE.
First,
I will review our progress on commitments made at the August 2001 Arthritis
Advisory Committee. These ongoing safety
assessment programs include Phase III and Phase IV clinical trials, patient
registries, and our long term follow-up program in clinical trials.
Secondly,
I will review new safety assessment programs that we are undertaking. These will include programs to further expand
our safety databases, as well as to obtain specific follow-up on lymphoma
cases.
As
I review these programs, all of which are collecting data in patients receiving
REMICADE, you will see that many are designed to also include patients who have
not received REMICADE. These data are
important in helping to differentiate safety signals that may be associated
with anti-TNF therapy from those that occur as part of the natural history of
the disease.
In
the next series of tables I will review the status of ongoing safety assessment
programs, showing the status at the last committee meeting in August 2001 and
the status as of last week.
This
table reviews our Phase II and Phase IV studies in rheumatoid arthritis. The ASPIRE trial in early RA has completed
enrollment of 1049 patients, and all of these patients have completed one year
of study treatment.
The
Phase IV START study, designed specifically toe valuate safety, and the iRAMT
study evaluating methotrexate tapering have both completely enrolled patients
since the last meeting.
Two
Phase II trials in Crohn's disease, the ACCENT I trial in active luminal
Crohn's disease, and the ACCENT II study in fistulizing Crohn's disease had
both completed enrollment at the August 2001 Advisory Committee meeting. Since that time, ACCENT I has received
marketing approval for maintenance therapy in Crohn's disease, and for ACCENT
II the BLA has been submitted and has received a priority review status from
FDA.
At
the last meeting we reported that Centocor is sponsoring two patient registries
to evaluate long term safety in patients receiving commercially supplied
REMICADE, one in rheumatoid arthritis and one in Crohn's disease.
We
have now well exceeded our target of 5000 REMICADE treated patients in the
National Databank for Rheumatic Diseases Registry. We have also recently achieved our target of
5000 REMICADE or non-REMICADE treated patients in the TREAT Crohn's disease
registry.
We
will continue to enroll patients in these registries to compensate for the
expected attrition of some patients over time and maintain a minimum of 5000
active patients in each registry.
As
you saw in Dr. Boscia's presentation, both of these registries provided
valuable data for evaluating the occurrence of lymphomas in REMICADE and
non-REMICADE treated patients with these diseases.
When
combining the safety assessment programs that I have just described, a
substantial prospective safety database emerges. As of today, this includes approximately
13,000 patients who have received or are receiving REMICADE and approximately
15,000 disease matched non-REMICADE treated patients for comparative analyses.
I
should also mention that this database includes our long term safety follow-up
program which follows all patients who have participated in our clinical trials
for a period of five years following their study participation. In August 2001 we committed to developing
safety databases encompassing 12,500 REMICADE treated patients, and we have
achieved that goal.
At
the same time, we are also initiating new international patient registries to
further grow our safety databases. This
includes the APART registry, an RA registry in the U.S. that will enroll
another 2500 patients. With our colleagues
at Schering Plough, our REMICADE marketing partner in Europe, we are
participating in a consortium of existing RA registries in Spain, Germany,
Sweden and the U.K.
Finally,
also in collaboration with Schering Plough, we are creating a Crohn's disease
registry in Europe that will enroll approximately 4000 patients, and follow
them for five years. All of these
registries will enroll and prospectively follow both REMICADE treated and
non-REMICADE treated patients.
The
registries will also provide valuable sources to obtain additional details on
reported lymphomas. Importantly, we
should be able to compare lymphoma profiles when REMICADE is given with or
without other immunosuppressants, and also with patients who have not received
REMICADE.
In
more fully characterizing lymphomas, we will actively collect data on exposure
and latency, clinical presentation, histology, and EBV status, and treatment
and response to therapy. We will also
initiative surveillance in multiple health care delivery systems, such as HMOs,
to further quantify lymphoma risk and contributing factors.
In
considering risk management initiatives, we should recognize that REMICADE is
used by a well defined set of physicians.
REMICADE is used primarily by, and continues to be promoted to
sub-specialists, namely rheumatologists and gastroenterologists.
We
believe that sub-specialists are best able to make benefit risk decisions on
the appropriate use of anti-TNF agents.
In addition, the sub-specialist population can be readily targeted for
risk management initiatives.
This
was exemplified by the REMICADE TB education program that we conducted in
August and September of 2001. This
program targeted 7500 physicians who were responsible for treating over 90
percent of patients who were receiving REMICADE.
In
conclusion, Centocor remains committed to research and education regarding the
safety of REMICADE. As we have done with
TB, we will conduct risk management programs as specific safety issues arise.
With
regard to safety assessment, Centocor continues to grow its prospective safety
databases in rheumatoid arthritis and Crohn's disease. These include Phase III and Phase IV clinical
studies, international patient registries, and a long term safety follow-up
program.
As
of today, safety follow-up in REMICADE treated patients and non-REMICADE
treated patients is being conducted in nearly 30,000 patients. This knowledge base will continue to increase
in the future. We expect these programs
to provide approximately 100,000 patient years of prospective follow-up over
the next five years in REMICADE treated patients.
Although
most of our presentation today discussed risk, no benefit to risk profile can
be addressed without some mention of benefit.
Therefore, to close our presentation today, I would like to briefly
review some of the attributes of the efficacy of REMICADE in rheumatoid
arthritis and Crohn's disease.
The
ATTRACT trial was a Phase III, two-year, controlled study in patients with
moderately to severely actively rheumatoid arthritis despite methotrexate
therapy. After 30 weeks of treatment,
which was the primary endpoint for signs and symptoms, all four REMICADE
treatment regimens in combination with methotrexate produced reductions in the
signs and symptoms of disease activity, as measured by the percentage of
patients achieving ACR20 criteria. These
were significantly greater than the reductions achieved by patients receiving
methotrexate alone.
In
ATTRACT the changes in the Van de Heijde modified Sharp Score were used to
assess progression of structural damage due to rheumatoid arthritis over two
years. The median changes from baseline
in the total score at two years were 0.5 for all four of the REMICADE dose groups
combined, and 4.3 for the methotrexate alone group.
Thus,
there was little or no progression of structural damage observed in the
REMICADE treated patients over a period of two years.
REMICADE
is the only agent approved for improving physical function in patients with
rheumatoid arthritis. This figure
presents the data on the improvement in physical function as measured by the
Health Assessment Questionnaire or the HAQ Score averaged over the two years of
the ATTRACT trial.
The
lines represent the median improvement in the HAQ averaged over time bracketed
by the inter-quartile ranges. In short,
patients enrolled in ATTRACT who had longstanding disease and substantial
impairment in function at baseline, when treated with REMICADE, had a statistically
and clinically meaningful improvement in function compared with patients who
were treated with methotrexate and placebo over two years.
The
clinical benefit of REMICADE for Crohn's disease is substantial and
unique. This was initially demonstrated
in this Phase III trial in which patients with active luminal Crohn's disease
who were not adequately responding to conventional therapies were treated with
one 5 mg/kg dose of REMICADE or placebo.
Four
weeks later, over 80 percent of the treated patients achieved a definitive
clinical response, and nearly half achieved clinical remission. The relevance of this benefit is underscored
by the low placebo response rates observed.
The
importance of REMICADE maintenance therapy for luminal Crohn's disease was
demonstrated in our ACCENT I trial. The
proportion of patients maintaining clinical remission at week 30 was
approximately twice as great in the maintenance groups of either 5 or 10 mg/kg
administered every eight weeks compared with the treatment group administered
only a single 5 mg/kg dose of REMICADE.
Please note, there was no true placebo group in this study.
Likewise,
the unique clinical benefit of REMICADE for fistulizing Crohn's disease is
shown here. Two-thirds of patients who
received a three-dose induction regimen of 5 mg/kg of REMICADE at zero, two and
six weeks achieved the primary endpoint of fistula response, defined as a 50
percent or greater reduction in the number of draining fistula.
Furthermore,
more than one-half of patients who received REMICADE achieved complete response,
defined as absence of any draining fistulas, compared with only 13 percent of
patients who received placebo.
Now
REMICADE is already approved for this induction regimen, and Centocor presently
has a pending supplemental biologic license application under priority review
at the FDA for maintenance therapy for fistulizing Crohn's disease. Suffice it to say, for Crohn's disease,
whether luminal or fistulizing, REMICADE provides an important clinical
benefit, and fulfills an unmet medical need.
In
conclusion, REMICADE is highly efficacious for patients with rheumatoid
arthritis, luminal Crohn's disease and fistulizing Crohn's disease, and these
are patients who have failed conventional therapies.
Treatment
related serious adverse events do occur with REMICADE use, but they are
infrequent. Centocor remains committed
to continue to characterize the safety profile of REMICADE and implement
further risk management initiatives as needed.
We
also look forward to the FDA Arthritis Advisory Committee's and FDA's
deliberation, assessment and guidance with regard to the known but, more
importantly, potential risks of anti-TNF agents.
We
believe the benefit to risk profile for REMICADE for both rheumatoid arthritis
and Crohn's disease continues to be excellent.
I'd
like to thank you for your attention, and Centocor and its consultants will now
be happy to answer any of your questions.
CHAIRMAN
ABRAMSON: Thank you very much. May I ask first a question regarding
dose. Is there any difference between
the 3 mg/kg and higher doses with regard to either the opportunistic infection
or the lymphoma reports?
DR.
SCHAIBLE: Well, you saw the individual
cases for lymphoma in clinical trials, and the range there was the lowest dose
we have ever studied, which was 1 mg as a single infusion up to several doses
of 10 mg/kg. So, certainly, for lymphoma
there has been no relationship to overall drug exposure.
With
regard to opportunistic infections, in our clinical trials we have not seen --
We don't have that many opportunistic infections in clinical trials, and
haven't seen a dose relationship there either.
CHAIRMAN
ABRAMSON: Other questions? Dr. Gibofsky?
DR.
GIBOFSKY: It's been suggested by several
speakers today that we ought to be cognizant of the effect of prior concurrent
DMARD immunosuppressant therapy on the subsequent development of lymphoma.
I
am intrigued by the data that you showed in slides 8 and 9 showing that in the
placebo groups, presumably matched for DMARD use and other variables, there
were no cases of lymphoma development.
It was only seen in the populations taking REMICADE.
To
what extent does that discount, if you will, the dispositiveness of prior
concurrent immunosuppressive or DMARD therapy in the development of lymphoma?
DR.
SCHAIBLE: I think, as Dr. Boscia touched
on in his presentation, if you look at the absolute placebo exposure in our
studies, it's less than 20 percent compared to the overall REMICADE exposure. So I think a major interpretive problem
occurs by the large discrepancy in exposure between REMICADE and placebo
treated groups.
So
it's very difficult to interpret that data or to evaluate the point that you've
raised.
DR.
KROOK: A follow-up on that
question: Are those people on the
placebo arm now receiving REMICADE? Is
that the reason for the small number, that they have crossed over? In other words, the number that's in the
placebo will really not change over time greatly.
DR.
SCHAIBLE: That's correct. That's actually static right now, because most
of those patients do cross over ultimately, and they are censored at the point
of time that they cross over.
DR.
KROOK: So in these groups, as they are
listed here, actually, the placebo group is almost at its maximum?
DR.
SCHAIBLE: It will --
DR.
KROOK; It will increase some.
DR.
SCHAIBLE; It will increase minimally,
because those patients are followed through five years after their initial
treatment in the clinical trial, but it will be minimally.
DR.
KROOK: But they have been crossed over,
if I'm right?
DR.
BOSCIA: Right. It's much worse in the Crohn's disease
population than in the RA population, because, of course, there are other
therapies to treat patients with rheumatoid arthritis. For Crohn's disease, you saw our -- We don't have
much placebo follow-up. There's nothing
else for those patients to use. So --
DR.
KROOK: Well, I would suspect also in
this group, as you see the effect and as a clinician, you will cross them over
when supposedly the study is done. I
mean, that's what most clinicians would do.
DR.
SCHAIBLE: I agree. Yes.
CHAIRMAN
ABRAMSON: A question that may be best
directed to Dr. Wolfe, and he may not have the information. But the issue of having a comparable patient
cohort, obviously, has been raised several times, and the Leflunomide treated
patients would be of some interest, because they typically have similar
indications -- that is,people who are failing to respond to methotrexate over
the last several years.
I'm
wondering, Fred, if you looked at that cohort as a comparator with malignancy.
DR.
BOSCIA: Hey, Fred, I think that
microphone will work right in front of you.
There were 58 patients treated with Leflunomide in the --
DR.
WOLFE: Actually,I have not officially
looked at it. It's part of the group
which was classified as no therapy. So
within that group the rates seem to be somewhat lower, but there is -- To some
extent, it depends on how you define exposure in that group as a whole, and we
didn't -- We took the entire time in the data bank as the exposure rather than
a specific time on Leflunomide.
So
I can't comment at this moment on the Leflunomide, but the data are available.
DR.
BOSCIA: I misspoke. When I said 58 patients, I was thinking of
Teneret, not Leflunomide.
CHAIRMAN
ABRAMSON: Dr. Day?
DR.
DAY: Concerning risk management, you
mentioned that REMICADE is prescribed primarily by sub-specialists, namely
those who are best able to determine the benefit risk profile. Do you have any ballpark numbers of the
percentage of prescribers who fall into that category?
DR.
SCHAIBLE: It's over 90 percent
DR.
DAY: Thank you.
CHAIRMAN
ABRAMSON: Yes, Dr. Anderson?
DR.
ANDERSON; I have a question also for Dr.
Wolfe relating to the registry data, national data bank on slide 15. I was wondering about the comparability of
the patient populations on the different drugs, whether differences in
demographics and maybe reimbursement and other things would affect whether
certain patients take -- which drug patients take, and what impact taking that
into account might have on the results.
DR.
WOLFE: Well, the REMICADE patients are
slightly older, but that would be reflected in the risk from the -- as adjusted
from the SEER database. There are
independent risks associated with age, with sex, and with education, and those
are the effects that we could see at this time.
Any other information on that?
Okay.
CHAIRMAN
ABRAMSON: Dr. Manzi?
DR.
MANZI: I would like to just make a
general comment and then a question. But
I think that there is a tremendous amount of data that could be mined form
these large registries that have comparator populations, which is something we
are all saying that we need.
When
I look at what the advantages would be, certainly, the number of patients that
are in these registries is tremendous. I
mean 18,000. Secondly, it represents, I
think, more of what the general use of these drugs are than possibly the
artificial environment of clinical trials, although you get important
information from those as well.
I
guess, lastly, it is certainly an advantage over passive surveillance and
counting on people just reporting. So I
would have a lot of questions for the owners of these registries that might
help us, because I think that information may be there that a lot of us need.
So
my question to our chair is: Do you
think this afternoon would be the appropriate time to have a dialogue with
people that have these registries in Europe and here as to how much information
we could get now from them that may be helpful?
CHAIRMAN
ABRAMSON: I think that's important and,
in fact, one of the questions is how we should go forward in capturing
information. So existing and novel ways
to do that, I think, is an important part of the discussion. Dr. Jaffe?
DR. JAFFE:
One issue that hasn't been brought out is sort of the change in
diagnostic criteria for the diagnosis of lymphoma over time. When I started in hematopathology 30 years
ago, a lot of what we call lymphoma today was pseudo-lymphoma or atypical hyperplasia
in the patient with rheumatoid arthritis.
So
I was just wondering with respect to some of the registry data whether that is
reflected by an increase in incidence in lymphoma over time due to change in
diagnostic criteria that may not be real?
DR.
WOLFE: I'm afraid I have no information
on change in diagnosis over time. The
registry -- If you recall it, REMICADE has only been out for about four years. I am not sure that there would be any change
in diagnosis, except that the rate in the SEER data banks has been increasing,
and this reflects the rate that everyone else used up to now.
DR.
JAFFE: Well, I think it's just a caution
that, if you are going to use historical data to compare incidence figures, you
have to be careful as to what the diagnostic criteria were used.
CHAIRMAN
ABRAMSON: Especially in concepts of
regression and the notion of pseudo-lymphoma and Sjogren's and what-not.
So
we thank you very much. We are going to
change the agenda slightly. We are going
to break for lunch now and have the open public hearing when we return at 2:00
p.m. So thank you very much.
(Whereupon,
the foregoing matter went off the record at 1:11 p.m.)
A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
(2:09
p.m)
CHAIRMAN
ABRAMSON: We would like to begin the
afternoon session. So can people please
take their seats.
We
are going to begin the session this afternoon with the open public hearing, and
we have four -- five individuals who would like to speak, and our first guest
is Mr. Rodger deRose who is President and Chief Executive Officer of the
Crohn's and Colitis Foundation of America.
Mr. deRose.
MR.
deROSE: Thank you, Mr. Chairman, and I
would like to thank the committee for giving us the opportunity to share our
thoughts. I know that I submitted a
paper to you several weeks ago, and I don't want to read that to you. I'll just give you an executive summary of
that, and then would like to introduce Rachel Hettich, one of the Crohn's
patients that we have had some association with over the years.
First
of all, let me say that I don't come from the medical or scientific community
like many of you do, but I did stay at a Holiday Inn recently. So I guess that qualifies me. No, I personally come out of the private
sector and retired about 18 months ago to join the nonprofit world and try to
leverage my business skills to help them manage their business more
effectively.
The
CCFA, Crohn's and Colitis Foundation of America, has been in existence since
1967. We have raised over $200 million
during that time and put that into mission critical programs such as research,
education, and support, and we really believe that we are one of the voices of
the million or so Americans that suffer from Crohn's and colitis.
As
you know, these are chronic intestinal diseases that share common
symptoms. They are referred to as
inflammatory bowel disease or IBD for short.
I am really appearing before this committee, because one of the medications
under discussion is the first therapy to receive your approval, the FDA
approval, for the treatment of Crohn's disease, and the drug, of course, is
what you heard earlier, infliximab, REMICADE marketed by Centocor.
At
this point, I want to note for all of you, just so that you are aware of the
arrangements that we face and we have with Centocor, is that they do sponsor
some of our education and awareness programs.
In 2002, of the $22 million in revenue that we generated, they
contributed about three-tenths of one percent or about $152,000.
The
majority of our dollars come from the patient community and major donors, and
in 2003 we are projecting that the contribution from Centocor will probably be
in the three-tenths of one percent as well, and our revenues are expected to
grow to about $26 million this year.
I
also want to mention that we do have currently a co-branding commercial on air
right now with Centocor, and I want to make it very clear to you that this is
not an endorsement. From our point of
view, this is a way in which the Crohn's and Colitis Foundation of America can
add additional information to the patient community, because when they call in
to the fulfillment number, they get in that packet additional information about
the CCFA as well as all medications, treatments, therapies, about the disease,
talking about all drugs.
So
I look at it as total patient care in terms of information and knowledge. I think, as you look at our patient
community, they probably are one of the most knowledgeable with regard to this
disease as well as the medications and therapies that are available to them.
One
of CCFA's most important roles, we feel, is to provide our patient community
with accurate and up-to-date and unbiased information about the treatment
options that they have. If you look at
all of our literature, you will clearly see that.
The
statement that I am making today and the one that I submitted is one that has
been approved by our National Scientific Advisory Committee, which is made up
of some of the thought leaders, certainly, in the industry, in the field of
IBD.
I
want to mention that Crohn's and colitis as a disease, if you are not familiar
with it, is -- It's a life altering disease, and it's notoriously difficult to
deal with and treat, and the symptoms include significant abdominal pain, severe
diarrhea, sometimes patients that have to use the restroom 15 to 20 times a
day, fever, and malnutrition. It's not
unusual to see an 18-year-old that looks like he or she is 12 years old,
because they can't get the nutrition into their body.
Over
time, we know that there are other symptoms that occur, such as they become
higher risk candidates for colorectal cancer, can lead to liver disease and
arthritis as well. And as yet there is
no cure, and it is oftentimes that Crohn's patients need to have surgery.
As
I have crossed the country talking to patients, one of the patients that I've
talked to that had the most in surgeries had 23, and it's not uncommon for a
Crohn's patient to at least have one surgery in their lifetime, and still it's
common for the disease to reoccur.
Now
there are a wide spectrum of IBD patients.
So their therapy must be tailored to the individual, and we recognize,
as many of you do, that infliximab is a very powerful drug. We know that, and that it is only for
patients with moderate to severe Crohn's disease who don't respond to
conventional therapy.
It
is also indicated, as you saw, for patients that have fistulas, which is a very
painful complication as well. But when administered to the right patient by an
experienced physician, it can mean the difference between constant suffering
and at least an active, healthy lifestyle and a productive lifestyle.
I
think, if patients are properly selected, the benefits certainly outweigh the
potential risks.
Now
it's important to note, and I know that all of you are aware of this as
professionals in your field, that infliximab doesn't work -- doesn't always
work for every patient and doesn't fit every profile. However, we are greatly encouraged by some of
the additional new medications that are coming to the field, and I know you
were talking about some of them this morning that are currently in the
pipeline, and many of these being biologic therapies that we are anxious to see
come to market.
We
must emphasize that, like all of you in this room, that we as the patient
community, as a patient advocacy group, believe that patient safety must never
be compromised. All therapies, from
those that are currently on the market as well as those that are being fast
tracked, need to continue to be researched for efficacy and safety, and we know
that you have stringent procedures in place to do that.
So
at a high level, that is where the Crohn's and Colitis Foundation stands on
this. I thought it would be very
interesting for you to hear from a patient that was diagnosed with Crohn's at
the age of eight. Rachel is 18 now, and
she has been on REMICADE for three years.
Rachel.
MS.
HETTICH: My name is Rachel Hettich. I am 18 years old, and I have Crohn's
disease. I was diagnosed when I was
eight years old. I had just started the
third grade and began to have constant stomach pains. I lost weight very rapidly and noticed a
decrease in my energy.
At
first, I was able to keep up in school, but things just kept getting worse and
worse. The pain from my stomach aches
was excruciating and very draining, both emotionally and physically. Dealing with it 24 hours a day was very
frustrating.
Basically,
it shut down my life for long periods of time.
Just making it through a whole week of school was a huge
accomplishment. I don't really remember
it now, but my parents tell me that most of the summer I was curled up on the
edge of the couch in pain for hours and even days at a time. My whole life would just shut down, and so
would my family's.
To
control the severity of my disease, my doctor tried a variety of medications
and treatments, including Asacol, Pentasa, 6-MP, MG-2 feedings, central IV
lines, and even several surgeries.
Finally, after much consideration, my doctor recommended trying
REMICADE.
My
first treatment was three years ago when I was a sophomore. We knew there might be some risk with
REMICADE, but we really had no other choice.
Living with Crohn's disease is like crossing a raging river by walking
across on logs. You put your foot out
and just hope that there will be another log to step onto.
When
they finally put me on REMICADE, the difference was like night and day. I was back in school and acting more like
myself. I gained back my energy and
weight as well as a healthier appearance.
I could eat just about anything, which was a major deal for me. It was wonderful.
It
only takes a few days after my REMICADE infusions for me to begin feeling
better. It's like a switch that gets
flipped on.
On
behalf of all people who suffer with IBD, I would like to express sincere
appreciation to all the researchers who work so hard to improve the quality of
our lives. I look forward to the future
with great anticipation of medical breakthroughs that may not only treat the
symptoms of IBD but perhaps even cure the disease. Thank you.
CHAIRMAN
ABRAMSON: Thank you, Rachel. The next speaker is Ms. Timms-Ford.
MS.
TIMMS-FORD: Good afternoon. My name is Betty Timms-Ford. I'm from Denver, Colorado, and I am here today
representing myself, although my travel expenses to attend this advisory
committee meeting are being paid by Abbott Laboratories.
I'm
here today to share my experience with rheumatoid arthritis and HUMIRA, a
medication that has greatly improved my RA and given me back the active life I
had before RA took over my day to day existence.
In
April 1990, as a 48-year-old woman, I noticed swelling and redness in my
knuckles, and at the same time started experiencing some pain. I visited an internal medicine doctor who
initially diagnosed rheumatoid arthritis but referred me to an arthritis
specialist who, after various tests, confirmed that I did indeed have RA.
My
doctor initially prescribed mild medications which seemed to have little effect
in relieving my pain and swelling, and my RA continued to worsen. He referred me to a physical therapy clinic
where they started me on various exercises in an attempt to keep my joints
mobile.
They
gave me adaptors for my car keys, toothbrush, and even pens and pencils, as I
was unable to close my hands enough to grip these items without aids. At this point, my day to day existence
consisted of rising, preparing myself for work, working an eight-hour day,
coming home, climbing the stairs and going straight to bed.
At
my desk at work, the pain in my feet was so severe at times that I used a
pillow on the floor as a cushion for my feet.
Rising from most any chair at home required my husband's assistance, and
on days I felt good enough to grocery shop, I would use the shopping cart to
steady myself and wrap my arm around items on the shelf and drop them into the
cart.
My
doctor tried numerous medications, hoping to find the right one for me. My RA did improve, but I was never able to
completely recapture the energy level I had before developing RA. That is, not until I started in the HUMIRA
drug study program in August of 2000.
I
never gave up on incorporating some exercise routine in my lifestyle, but since
starting HUMIRA, it is very rare that I experience any pain, and I am now,
weather permitting, walking two to three miles most days on my lunch hour, and three or four nights each week
after working eight or nine hours, I head straight to the gym and work out for one,
one and a half hours.
If
an occasion arises, I tell people I have RA.
Their response is almost always, I never would have guessed; you
certainly don't exhibit any signs of arthritis.
I
also have been able to involve myself in a lot of volunteer work that I was
doing previously until my energy level was drained so severely. I consider myself extremely fortunate that I
was blessed with an inordinate amount of energy and also found a wonderful
doctor who was willing to involve ;me in the HUMIRA study program.
HUMIRA
has had a tremendous impact on my life, and I appreciate the opportunity the
committee has given me to share my story during your meeting, as I think it is
important for others to know how invaluable this drug has been for me and,
undoubtedly, would be for others suffering from RA.
Thank
you for your time and attention.
CHAIRMAN
ABRAMSON: Thank you very much. Lucille Cerretta.
MS. CERRETTA: Hello.
Thank you for having me
today. My name is Lucille Ann Cerretta,
and I'm here to share my personal experience with rheumatoid arthritis and
HUMIRA.
Abbott
Laboratories has provided my travel so that I could attend this meeting.
I
am a 50-year-old woman, and I was diagnosed with RA when I was 37. I have been on a host of drugs over the
years, including prednisone for more than a decade. None of these treatments had the results of
HUMIRA, and some almost took my life.
Not
only did I have to fight the pain of RA, I had to live with the side effects of
those medications. I am finally off
those drugs, thanks to HUMIRA.
The
pain and suffering I had to ensure are really hard to capture as I stand here and speak to you. I was unable to work, and had to live on
disability. That alone is a
challenge. Try living on $500 a month.
I
turned to art to ease my pain. I used
modified brushes that were built up so I could hold them. I would go to Home Depot and buy tubing that
was about this big, and I would start to paint.
Today,
with HUMIRA, I am exhibiting my artwork, standing at exhibits, carting
paintings in and out of my van, and carrying them into galleries. I'm in two galleries right now that are
upstairs lofts. So I have to carry my
paintings up the steps, and I do it.
Not
only do I feel better, but I am no longer using a cane, looking at scooters to
buy or sleeping with a brace. I also
appears that I have had improvement or reversal in some of the damage
done. I am now down to wearing one brace
on my fingers, where before I needed four.
I
have experienced a hard life, but I am a positive person and always believed
research would someday find an answer to this crippling disease. I only wish I was just now being
diagnosed. Today people with RA have the
option with HUMIRA that allows you to continue living the life you already
have. I didn't have that option until
two years ago.
I
am so grateful that RA patients now have a treatment like HUMIRA. Without it, myself and RA patients like me
would revert back to being dependent on others, and nobody wants to do that.
Thank
you for allowing me to share my story with you today. I really appreciate it. Thank you.
CHAIRMAN
ABRAMSON: Thank you very much. Judy Levinson.
MS.
LEVINSON: Good afternoon, Mr. Chairman
and members of the Food and Drug Administration. My name is Judith Levinson. I am a 58-year-old individual who has
suffered with rheumatoid arthritis for 18 years. I have been on the drug Enbrel since January
7, 1999.
Since
that time, I have administered approximately 431 shots. I am not a paid spokesperson, but I do own
Amgen stock. I purchased it two weeks
after I began my treatment, because I had such confidence and trust in this
drug and this company.
Some
of you might remember me from April 11, 2000, when I asked for your approval
for newly diagnosed patients to have the opportunity to receive Enbrel as part
of their treatment. I applaud you for
making that possible.
On
August 17, 2001, I spoke to you regarding safety of Enbrel. These ongoing reviews of new biologic
modifiers is essential to protect all individuals from potential harmful side
effects.
One
recommendation was for doctors to encourage their patients to be tested for
TB. I took that advice, and my TB test
was negative. Enbrel patients are also
advised by the inclusion of information packets in the dosing boxes to immediately
notify their physicians about any serious infection they may experience.
I
told you about my 14 surgeries I have undergone to correct hand, wrist and foot
deformities caused by severe RA. Over
the past 18 years I have taken many prescribed drugs, some of which have caused
serious side effects, including nausea, fluid retention, puffiness, stomach
distress, and headaches.
I'm
happy to say that on Enbrel I have experienced none of these problems nor have
I had any infections, not even a single cold.
Every two months I undergo complete blood panels to evaluate the status
of my health to ensure that I am remaining within the parameters of normal
levels.
Amgen
is diligent with respect to keeping their users informed about any findings
regarding Enbrel. I have every
confidence that Enbrel is safe and that, if any problems should arise, I will
be notified immediately to contact my doctor.
Approximately
100,000 people now benefit from this incredible drug. To me, Enbrel has been a miracle. It has given me back my life. Before taking Enbrel, I visualized myself
requiring assistance even to do the simplest of tasks, but not now.
Today
I am a productive individual, a wife, a mother, a daughter, and a sister. I'm a published poet and a fused glass
artist. Around my neck I am wearing my
signature piece, a wounded dove, made from small bits of glass that I designed
with these hands. Enbrel has restored my
strength, stamina, and allowed me to forgo my afternoon naps, giving me a
better quality of life than I ever thought was possible.
My
husband calls me his energized bunny, because I am always in the go mode. I am always amazed by people I meet who
either know someone using Enbrel or want to know about the benefits of this
drug.
Last
week, I met someone whose brother has RA and is being treated with bi-weekly
injections, and she said that he has been given a second chance to life.
The
safety of all drugs is extremely important, and it is very reassuring to know
that you, the FDA, considers it such a high priority. I'd like to thank you allowing me to speak to
you today.
CHAIRMAN
ABRAMSON: Thank you. We thank each of the speakers. I think it is so important for us. The courage that you all show is -- we need
to be mindful of that, and because our charge is to look at the benefit and the
risks of these medications, and I think hearing a person's story can bring home
to us as physicians and others the details of this condition that we can't read
particularly in the papers and the dossiers.
We
have one more public statement to be read in by Ms. Reedy from Colleen Andrus.
MS.
REEDY: Colleen Andrus writes: "I am currently a patient with
rheumatoid arthritis and am on a regimen of Enbrel and Arava. My attending physician is Dr. Michael Schiff
at the Denver Arthritis Clinic.
"I
understand that Enbrel is set for review and evaluation this year, and am
writing in support of this wonderful medication. I am 54 years old, and was diagnosed with RA
about five years ago. Treatment has involved
several different RA drugs prior to Enbrel, all of which were eliminated for my
treatment, either because they did not relieve symptoms or I had some type of
adverse reaction.
"I
began injections of Enbrel in July of 2001, and my quality of life has improved
significantly. I have had no side
effects, nor site reactions. It is quite
reassuring to know that there is treatment upon which I can depend, and that I
can continue a fairly normal lifestyle.
I have always been very active, and the problems with RA have been
challenging.
"Although
I have not yet experienced any serious joint deterioration, I found that
fatigue and moderate to fairly severe joint pain was constant without
Enbrel. My grandmother suffered form
severe debilitation from RA, and, of course, I am concerned that my condition
will progress. To date, I am happy to
report that my current treatment seems to be very successful, and progress of
the disease seems to be inhibited by my current drug regimen."
Her
next paragraph addresses the difficulty in opening the vials and in piercing
the caps with hypodermic needles. Take
note. She closes:
"I
hope that Enbrel will continue to be approved by your agency, as having a
choice of treatments is very valuable to those of us with RA."
CHAIRMAN
ABRAMSON: Thank you. We are now going to enter the segment of
addressing the questions put to the committee, and Dr. Siegel will introduce
the questions. Then I think what we will
do is the panel will have a discussion of each of -- There are six questions
pertaining to lymphoma. As we go through
each one, the panel will make their comments, and then if any of the sponsors
would like to make a comment after we discuss a point, you are welcome to sort
of come to a microphone and make a statement or a clarification.
So,
Jeffrey, would you like to begin, please.
DR.
SIEGEL: Thank you. I want to make a few concluding remarks, and
then discuss the questions that we wanted to pose to the committee.
Before
we begin, I wanted to just review some of the data for lymphomas. We have asked the panel to concentrate
particularly on several different adverse events, and we have presented a lot
of data over the course of the morning.
So I thought it would be helpful to just review some of the key data.
We
have presented two different analyses for you for each of the products. One is an analysis of the controlled portions
of the controlled trials where we think the experience is comparable between
drug and placebo. Separately, we have
presented data from the overall database, including the standardized incidence
ratios.
For
adalimumab in the controlled portions of the clinical trials, two cases of
lymphoma were observed among 1380 patients who saw a mean exposure of 0.6
years. In the placebo control arms of
these trials, zero cases of lymphoma were observed among 690 patients with 0.5
years mean exposure.
In
the overall safety database for adalimumab, ten cases of lymphoma were observed
among 2400 patients. This was over a
course of 2.4 years median exposure, and a calculated standardized incidence
ratio of 5.42 was calculated with confidence intervals as shown on this
slide.
By
the way, all of the data that I am going to be showing you in these first
slides is in your handouts, but these slides are new, just to place it in
summary form.
For
etanercept, one case of lymphoma was observed in the controlled portions of the
clinical trials in the etanercept arm, among 2502 patients receiving a mean
exposure of 0.5 years.
In
the placebo arms of these trials, no cases of lymphoma were observed among 921
patients with a mean exposure of 0.5 years.
In
the overall etanercept database, six cases of lymphoma were observed among 3389
patients receiving a mean exposure of 2.2 years. The standardized ratio here for the total
database was 2.31, with the confidence intervals as shown on the slide that do
overlap one, 0.85 to 5.03.
Finally,
for infliximab, in the controlled portions of the clinical trials, three cases
of lymphoma were seen among infliximab treated patients, among 2421 patients
who received a mean exposure of one year.
In
the placebo control arms of those same studies, there were no cases of lymphoma
among 489 patients with a mean exposure that was similar to the infliximab
group of 0.9 years.
In
the overall safety database for infliximab, six cases of lymphoma were seen
among 2421 patients receiving a mean exposure of 1.7 years. The standardized incidence ratio here for the
infliximab database was 6.98 with the confidence intervals that exclude one,
namely from the lower bound of 2.56 to 15.19.
So
in summary, the newer data that we have presented show an occurrence of
lymphomas with each of the approved TNF blocking agents. In controlled trials, we see one to three
cases of lymphoma with the study drugs versus none with placebo.
In
the controlled plus the non-controlled extension trials, we saw a higher rate
of lymphomas than observed in the general U.S. population, based on comparison
to the SEER database, and additional cases of lymphoma have been observed in
the post-marketing experience.
It
is important to keep in mind, as you have heard several times over the course
of the morning, that higher reported rates of lymphoma have been observed in RA
patients, and this clearly complicates the analysis.
In
terms of congestive heart failure, the data you've seen this morning suggested
deleterious effects of infliximab in congestive heart failure patients, and
data from the etanercept trials showed some concern in trends in congestive
heart failure patients receiving etanercept.
We
don't know what the effects of adalimumab are on similar congestive heart
failure patients, because studies are unavailable.
So
in conclusion, the approved TNF blockers are associated with high ACR response
rates in rheumatoid arthritis and beneficial effects for progression of
structural damage.
For
infliximab, there is also an additional prove claim of improvement in physical
function as based on the Health Assessment Questionnaire, based on data from a
long term study. Data for this same
improvement in physical function are currently being collected for the other
TNF blockers.
A
number of serious but uncommon adverse events are also associated with the use
of TNF blockers, and for some adverse events these risks can be reduced with
appropriate screening.
Turning
to risk management, it is, of course, important to maximize the benefit of
treatment with these agents and to minimize the risks associated with their
use. For the identified risks of TNF
blockers, it is important to collect data to accurately assess this risk, to
minimize those risks where appropriate by patient selection and screening, and
by appropriate risk communication.
So
finally, the agency welcomes discussion on the part of the Advisory Committee
regarding lymphoma of the confounding factors in assessing causal
relationships, in the Advisory Committee's assessment of the likelihood of
causal relationships between lymphomas and TNF blocking agents.
We
welcome their advice on how to collect data that would help assess causal
relationships, and on selection of appropriate language for package labels to
communicate the available information.
Regarding
congestive heart failure, we welcome discussion of approaches to risk management. Thank you very much.
CHAIRMAN
ABRAMSON: Thank you. What I will do is read the first question and
then open it for discussion to the panel members.
Question
Number 1: Please comment on the
characteristics of the cases of lymphomas -- that is, age at time of diagnosis,
distribution of non-Hodgkin's lymphoma versus Hodgkin's disease, histology,
etcetera -- observed in patients treated with TNF inhibitors relative to the
experience in the general population and relative to the experience in people
with underlying rheumatoid arthritis or Crohn's disease.
What
I'd like to do to begin is that we have three experts, particularly in the
field of oncology and lymphoma, Dr. Blayney, Krook, and Jaffe, and I would ask
first to solicit their opinions. Then we
can open up for more extended discussion.
Dr. Jaffe?
DR.
JAFFE: With respect to the first
question, I think, unfortunately, we don't have a lot of the data that we
really need to answer this question. I
think most of the lymphomas that have been reported in the session today and in
the literature have not been adequately studied so that we can draw definitive
conclusions. But I think, based on the
data available, I would say that the pattern of lymphoma occurrence is similar
to what one observes in rheumatoid arthritis and less similar to what one sees
in the general population.
In
general, the proportion of non-Hodgkin's lymphoma to Hodgkin's disease tends to
be somewhat higher, as it is in the rheumatoid arthritis patient population,
and the overall incidence of follicular lymphoma, the most common lymphoma
subtype in the United States, is relatively low.
So
I think, from my perspective based on the data, it resembles the pattern of
lymphoma that you see in rheumatoid arthritis.
With
Crohn's disease, those cases have not been extensively studied. There are small incidences of lymphomas
associated with immunosuppression, and those are sometimes Hodgkin's and
Hodgkin's-like lymphomas as well as large cell lymphomas.
CHAIRMAN
ABRAMSON: So from a pathological
perspective, the issue had raised whether patients with immunosuppression
develop a certain kind of lymphoma. Are
you also saying that this is not the kind of lymphoma that these people are developing?
DR.
JAFFE: No. I think some of the lymphomas that are seen
in rheumatoid arthritis are related to the other therapies that are used, in
addition to the underlying disease. So I
think we have two confounding variables when trying to look at these particular
drugs that we are considering today.
One
is the other agents such as methotrexate and to the lymphomas that occur
sporadically as a consequence of the disease itself. I think the Hodgkin's and Hodgkin's-like
lymphomas and large cell lymphomas are the ones that are generally related to
the immunosuppression.
CHAIRMAN
ABRAMSON: Thank you. Dr. Krook.
DR.
KROOK: I will echo some of Dr. Jaffe's
concerns. I know, as I look at all three
TNF inhibitors, generally they are older patients and generally they have had a
long duration of the rheumatoid arthritis.
Some
of the confounding things are, just as Dr.
Jaffe said, how long the other drugs which have been involved and where
it is. Now one of the other things that
in some of the documents which I received there were some of the follow-up on
this. If I remember right, there were
not very many deaths. They were treated
and did fairly well, and I think that that relates to that also.
I
think that, if you look at the incidence of Hodgkin's in the overall
population, it is probably similar, one Hodgkin's or two Hodgkin's to nine or
ten of the other, and I think that is very similar.
I
think the other thing is that we just need to see what happens with these
people, whether they act the same as others.
But again, this is a heavily pre-treated group of people. My impression is that it is very similar to
what one sees in the overall population.
CHAIRMAN
ABRAMSON: Dr. Blayney.
DR.
BLAYNEY: I'm struck by what we don't see
here. As Dr. Jaffe pointed out, we don't
see follicular lymphoma, and we don't see a lot of Hodgkin's disease. What we do see is lymphoma that seems to be
related to the background incidence in rheumatoid arthritis, and perhaps in
these heavily pre-treated patients or these advanced disease patients, it's
very difficult to sort out which is which.
There
is some acceleration in the underlying propensity to develop lymphoma of the B
cell, large cell type. Furthermore, we
don't see Kaposi's sarcoma, and we don't see an excess of melanoma. Perhaps these people aren't exposed to the
Kaposi's sarcoma infectious agent and aren't exposed and develop Kaposi's
sarcoma. So I find that reassuring.
The
third thing we don't see in the heart failure trials, or at least we didn't
hear about it in the heart failure trials, was lymphoma developing in patients
with heart failure who are exposed to these agents, albeit for six months to 12
months. So I find that data reassuring
as to the safety of these compounds as a class.
There
may be some difference among the three that needs to be explored, but I
basically am reassured by what we don't see.
CHAIRMAN
ABRAMSON: Thank you. Other comments from members of the
panel? Dr. Williams?
DR.
WILLIAMS: As I have had the chance to
review the extensive materials and listen today, I don't see that I can expect
anymore incidence of lymphoma with etanercept than I would based on just the
incidence we see with rheumatoid arthritis.
There may be perhaps some increase with monoclonal antibodies, but even
that is in patients with chronic inflammation and who have been exposed to
other immunosuppressive agents, and I don't think causality can be determined
at this time.
I
thought the statement that was made in adalimumab's labeling was very fair in
terms of notifying people what the potential was, but we need much more data
before we can say it was caused by these drugs.
CHAIRMAN
ABRAMSON: Other comments?
DR.
MAKUCH: Just a few comments, one of them
being: I think, actually, that the SIRs
are actually perhaps even more comparable than what was just given in the
summary, as I know that for Enbrel the one given to us was 2.3, but on the
other hand, I think there is some going back and forth on whether it really is
six or nine cases, in which case for nine cases then you do have a significant
SIR of 3.47.
So
it seems as if one of the things I wanted to make a comment about is, I guess
-- or raise, is the issue about a class effect versus individual drug
effect. When I do look at, especially
with the Enbrel alternative, SIR 3.47, they all seem to coincide with one
another.
The
second comment was, I guess, looking at it a different way but sharing the
remarks of everyone else up to this point, we really didn't see information
about concomitant meds. We really didn't
see, despite numerous questions earlier, about duration of treatment or dose,
other prognostic features.
So
it really then is very difficult to separate out the underlying association
between the lymphoma cases in RA versus the lymphoma cases with respect to it
being due to these drugs.
I
think the final remark is regarding the length of follow-up. I did hear the entire morning that the risk
is constant over time and, if you do believe that the risk is constant over
time, then I think the data that we see are fine.
If
you do not believe that the risk is constant over time, and looking at some
things, I think it might not be -- it may increase over time. If that's the case, then what we may be
seeing would be then an underestimate of the risk associated with these
compounds in their relationship to lymphoma.
So
I guess the summary comment is just some of the things that we did not see are
actually fairly uniform SIRs among the
three, indicating at least some discussion about a class effect, and finally
the effect of length of follow-up on the true risk if you do not believe that
the risk is constant.
CHAIRMAN
ABRAMSON: So if we can go back just to
the first point number one question on the histopathology, is it fair to say
that, in summary, the kinds of lymphomas we are seeing are consistent with
those that we have seen in the past in rheumatoid arthritis patients, which
differ a little bit from the normal population where you see more follicular
cell. So, therefore -- and there is
nothing distinctive that we are seeing that says it's a third class, a
different kind of tumor that might be peculiar to this class such as we see in
HIV or what-not.
So
it's consistent with the disease historically.
Is that a fair summary? What we
have observed in the disease in the past --
DR.
JAFFE: What we have observed in the
disease, both sporadically and with given therapies; in other words, I think
that some of what we see is related to other therapies that are used for the
disease.
CHAIRMAN
ABRAMSON: Right. So without ascribing causality, it's just the
histopathology is consistent with RA and treated RA.
Any
other comments on the point one from the committee members? Yes?
DR.
ILOWITE: Mostly a question. There was some discussion about EBV
histology, EBV genome in the tumors.
Would that be helpful in elucidating this issue?
DR.
JAFFE: No, I think those are the data we
need. I mean, I think that the
sporadically occurring lymphomas that you see in rheumatoid arthritis and those
associated with therapy are often EBV positive, particularly those occurring in
patients related to therapy, methotrexate and other immunosuppressive agents.
CHAIRMAN
ABRAMSON: Are there comments from any of
the sponsors with regard to this first question? Dr. Siegel, anything more on point number one
before we go on? Okay.
All
right. So question number 2, I'll read
again: Please discuss the strength of
the available evidence, including the pre-marketing controlled trial
experience, open label extension studies, post-marketing registry data, and
post-marketing spontaneous reports, incidence rates over time, etcetera, and
any conclusions you are able to draw regarding an association between
TNF-blocking treatments and lymphoma.
Once
again, I think I will begin the discussion with some of our experts in this
area perhaps, and that is Doctors Day, Elashoff, Makuch and Anderson in terms
of epidemiology and biostatistics. Then
we will open it up to other members of the committee. Dr. Day?
DR.
DAY: I have no comment.
CHAIRMAN
ABRAMSON: Dr. Elashoff.
DR.
ELASHOFF: Yes. To assess how either reassured or disturbed
we should be by what we see in terms of the lymphoma SIRs, I would need some
additional biologic medical information.
What is known or believed about how long -- what the latency is from the
time of some triggering event to diagnosis of lymphoma.
If
we were to conclude that these drugs were affecting it, would we be thinking it
was triggering the initial development or perhaps stimulating things? So if we think it is perhaps triggering it,
have any of these follow-ups really been long enough so that we would expect to
see anything yet?
So
I would need some discussion of that point in order to assess the data we have.
CHAIRMAN
ABRAMSON: Dr. Makuch.
DR. MAKUCH: I think, very briefly, the strength of the
available evidence -- I think there are some issues. One of them is just very small numbers. Just a few cases one way or another would
make a substantial difference. I think
that any kind of analysis in which you did vary this, sometimes called
sensitivity analyses, may lead to substantively different conclusions.
So,
therefore, the strength of the available evidence, to me, is not overly strong.
I
did mention as a second general category about evaluating the evidence,
concomitant meds, duration of treatment, dose, prognostic features,
etcetera. Without having more
information about that, one cannot reliably understand the extent or nature of
the association to any great degree.
Finally,
again getting at the constant risk -- and again I think Dr. Elashoff said the
same thing in a slightly different way of looking at the length of
follow-up. I really would have a much
higher comfort level with seeing data six months or a year from now in which
the length of follow-up is longer, and again because the -- If you do not
believe that the risk is constant over time, there may be an issue there.
I
would have liked all of the sponsors probably to have done one additional
analysis, which is called a hazard analysis, which is an explicit evaluation of
the risk question per se, which was
not done here.
CHAIRMAN
ABRAMSON: Dr. Anderson.
DR.
ANDERSON: I don't really have anything
to add to what Doctors Elashoff and Makuch have said.
CHAIRMAN
ABRAMSON: Are there other comments
people think the strength of the evidence -- Oh, okay, Dr. Krook.
DR.
KROOK: I think, as we look at this, and
the question is that the committee or whoever follows this is going to have
real problems, because you have three drugs here which are going to be used
fairly extensively in the community, and I think that is going to confound
things unless we have an older control.
But then we have problems with timing, all the other things that were
talked about, geography and otherwise.
My
own looking at this, the pre-marketing controlled trial is probably almost as
good as we are going to do and see what happens with these people. Unfortunately, I heard that most of the
placebo group has crossed over, and that's going to be a problem, because I
think you are going to see with that one even -- you are going to perhaps see a
few more lymphomas, as somebody said, down the line. One or two more lymphomas are going to change
the whole thing. We are going to get
away from the SIR. We are going to get
outside the confidence limits.
So
I'm not sure we can do much better than we are now. The other comment which is
interesting on post-marketing is I was impressed by the national database that
most of the adverse events were coming from patients, not from physicians and
whatever, although -- and that adds to the problem.
CHAIRMAN
ABRAMSON: Yes, Dr. Unger?
DR.
UNGER: I have a comment about one of Dr.
Fischkoff's slides with respect to the risk of lymphoma over time. I don't know if there is any way we could see
one of those slides or you could look in your packet, slide 43.
Dr.
Fischkoff presented this slide, and his interpretation was that the risk was,
in fact, constant over time. In my
examination of the slide, I arrived at a different conclusion, which is that I
see -- between day 620 and 840 approximately, I see five out of ten of the
cases of lymphoma in a 200 day period.
Now
I'm not a statistician, but you have 2000 days of follow-up. You have ten events. So if this were sporadic, one would expect
one event per 200 day period, and we are looking at five events in that period
of time. I'm wondering if anyone else
made that observation and if there are any comments about that.
DR.
MAKUCH: Which slide number are you
talking about?
DR.
UNGER: That slide. It's slide 43. I mean, the way the scale is drawn, it's hard
-- Aha. I have a pointer. In this area right here, there are five
events, and they occur 21 to 28 months after initial exposure.
A
related question that I have -- it's a rather provocative question, but being
that we have some epidemiologists here:
If one does something to cause cancer, if one blows up a nuclear device
or you have a Chernobyl and there's a bump in lymphomas, what is the lag time?
CHAIRMAN
ABRAMSON: Dr. Blayney, would you like to
address that? Dr. Blayney or Krook?
DR.
BLAYNEY: I think there's several answers
to that question. One, we are not -- The
cancers, as I understand them, that relate to damage from DNA from radiation
exposure and, by the way, from alkylating agents probably have a peak incidence
of five to six years after the treatment.
The
other -- and this goes to Dr. Elashoff's question, the best models of
immunosuppressed related lymphoma that I know are HIV. So HIV, you see the lymphomas way at the tail
end of the disease course when the immunosuppression is quite profound.
In
this instance, it depends on where you start the clock. Do you start the clock at the diagnosis or
rheumatoid arthritis and all of the other things that happen to a RA patient in
that time or do you start the clock when they receive the anti-TNF agent?
My
supposition would be, and my hypothesis would be to start the clock when the
rheumatoid arthritis diagnosis is made. So I think maybe a year of follow-up is
not going to be helpful, because that's a small percentage -- a small absolute
percentage of the time course when patients are at risk for developing one of
these lymphomas.
In
the transplant setting where you have iatrogenic immunosuppression, I don't
remember what the peak incidence is, but I think the point to your question is
there are a lot of different ways that people get secondary malignancies, and
here we are talking about an immunosuppressive event.
DR.
WEISS: In the transplant setting the
lymphoproliferative diseases that do occur tend to occur rather rapidly in the
course of disease, and oftentimes, too, those might regress once you remove the
immunosuppression. So they do seem to be of somewhat different character.
DR.
KROOK: Just interesting. In Doug's model there, if you start at the
time of the rheumatoid arthritis, you would have a curve that would certainly
stretch that farther out. I suspect this
is from the inhibitor.
The
other thing: I think on the slide that
was shown, if you can put it back up, there are some patients which are
probably back at day 800 and 1000, if I'm right. So you don't have all -- if I'm correct, all
2500 patients that are 2000 days out, unless I'm wrong. They may be thinking of cancer curves, but at
least usually there is a bunch coming along.
DR.
BLAYNEY: But if I may respond.
CHAIRMAN
ABRAMSON: Yes, go ahead.
DR.
BLAYNEY: to the left of that there is a
bunch of patients who never got to this, who may have developed lymphoma from
rheumatoid arthritis and didn't qualify for the treatment with the experimental
agent. So this sort of -- it doesn't
include -- there is a selected bias in this slide 43 against people who might
have developed lymphoma from the rheumatoid -- or the underlying condition or
its treatment, as Dr. Jaffe has pointed out.
CHAIRMAN
ABRAMSON: Dr. Fischkoff, did you want to
make a comment?
DR.
FISCHKOFF: Yes, a couple of
comments. Number one, the reason that we
presented the data this way is because, as has been discussed here, not all
patients have had equal exposure, and in order to correct for that, we thought
the Kaplan-Meier analysis would be the correct one to do rather than choosing
some arbitrary bins.
The
other reason that we also felt that that was an appropriate analysis is because
the shape of the curve that you get also depends on the selection of the
bins. If you look at it by years instead
of by six months, you see that there were three in the first year, four in the
second year, two in the third year and one later on, of course, recognizing
that not all patients have made it that far.
So
those are the two reasons for the one that you had brought up, and also because
there is also some effect of the way you choose your analysis bins on the shape
of the curve. It was our feeling that
this analysis correct for those kinds of effects.
CHAIRMAN
ABRAMSON: Yes, Dr. Makuch.
DR.
MAKUCH: I agree it does actually do a
nice job of showing that. I think the
issue was whether or not it is consistent with constant risk or not constant
risk. Actually, it took me about ten
minutes for my eyes to focus on the graph, but I think I can see it now, and I
would agree with you that -- because as you go through those bins in time,
there are fewer people at risk.
So
since all of a sudden, you are having that clumping between, let's say, 600 and
800 days with fewer people at risk, that really does indicate to me that there
might be an increasing risk for some period of time. If there is, then that figure actually argues
fairly persuasively for one to two-year follow-up as being necessary to perhaps
assess the full risk associated with what we are examining here.
CHAIRMAN
ABRAMSON: Thank you. Dr. Gibofsky.
DR.
GIBOFSKY: I share the concerns of my
colleagues across the table with regard to the caveats imposed on the strengths
of the data at the present time. That
said, I think we have to be careful not to confuse a temporal association with
a causal association. They are quite
different, both scientifically and to our patients.
That
said, I want to get back to Dr. Manzi's comment earlier, that if we are asking
these kinds of questions, we really do need to come up with the methodology and
the data to mine that will us be more precise in the answers that we want to
arrive at.
I
think one of our charges and one of the areas that we should be discussing is
what kinds of questions we should be asking, what kind of data we should be
collecting, what kind of standard information should be required.
I
was intrigued by Dr. Silman's comment that to use one of these agents in his
country, there is a requirement for a national registry. Perhaps we should be moving toward some kind
of effort in that regard. Dr. Wolfe has
certainly taken great steps in that direction, but it would be nice if we as a
group of concerned individuals and experts could prod our respective
professional associations and colleagues to a similar effort.
I
think that is how we are going to get a better handle and come back when we
revisit this as to what information we have collected and how the data looks to
us.
CHAIRMAN
ABRAMSON: Exactly. And that we need to get into a little bit
more as part of the next question. I
guess, what is the strength of the available evidence? Obviously, the committee feels that the
evidence -- there's not a lot of cases.
There's some issues -- there's clear issues of numbers and the need for
more data.
DR.
WILLIAMS: I would like to just reiterate
the comment that I think that the case, at least for etanercept, didn't make a
very good case at all right now. There
are no more expected than you would expect in a group of rheumatoid patients,
regardless of severity of disease. So
that it wasn't equal for all three groups.
CHAIRMAN
ABRAMSON: Right. So this is again a question. Are they equal? On the other hand, the signals are small for
each of the drugs, and it is striking that in the randomized trials you don't
see much emerging in placebo. Again, not
enough numbers to say causality but enough to say there might be a signal, and
I'm not sure. I'm curious as to what
other people think.
Dr.
Williams raises the point that is this more or less for one or other of the
drugs or simply can we say we have a signal emerging that needs more
information going forward? I'm curious
if people have comments on that.
DR.
WILLIAMS: Having made the point, I would
say that I would still survey all three drugs.
I would not eliminate etanercept just because it wasn't strong on that,
because it has a similar effect.
CHAIRMAN
ABRAMSON: Right. Okay.
DR.
KROOK: Certainly, we have a time
difference between the three drugs, you
know. The last one in is tomorrow.
CHAIRMAN
ABRAMSON: Right.
DR.
GIBOFSKY: One more comment, if I might. I think we also have to focus on the dichotomy
between the clinical trial and clinical practice. It was commented by one speaker that, in the
context of a trial where you have wonderful inclusion and exclusion criteria,
you are not always getting the real world experience. Our charge now is to come up with some
recommendations for the use of these drugs for our patients in the real world.
CHAIRMAN
ABRAMSON: Right, going forward. And I would like to just suggest perhaps to
the FDA that there are other drugs that were approved in the same time frame,
Leflunomide and Anakindra, indicated for similar kind of patient population,
particularly in the Phase III trials. It
would be very interesting to go back to some of the existing databases and see
what kind of signals emerge from those DMARDs.
Okay. So this is question number 2. Are there comments from any of the sponsors
regarding this question 2? Yes, Dr.
Boscia.
DR.
BOSCIA: Hi, Jerry Boscia from
Centocor. I just want to caution that
you have to be careful when you compare one sponsor's product to the next
sponsor's product to the next sponsor's product, because the patient
populations that each company studied weren't necessarily the same.
I
mean, Jeff would be the best person to comment on this, but I believe that --
and I don't know, Jeff, because I'm not privy to all the data, but some
companies studied patients with early RA more so than some of the other
companies studying patients with later disease, and I really think that makes a
difference.
DR.
SIEGEL: I think there is no doubt that
that could clearly make a difference. I
think the pattern that we are seeing with most of the products that have been
approved and that go through the pipeline is that sponsors initially study them
in DMARD failures, in people with more longstanding active disease, and after
they have shown efficacy in that population, then do a study on early
rheumatoid arthritis.
That
was certainly the case with etanercept, and I think we are seeing similar
patterns with some of the other products.
But at least early on, you will tend to see mostly data in more advanced
disease, longstanding disease.
DR.
WEISS: I think you also raise a good
point, that it will be important as we develop more data to see more of these
trials in early disease, of longer term follow-up, to -- just like the other
suggestions, to be able to try to characterize the patterns of adverse events
in, particularly, the lymphomas that we see, and see if they tell a compelling
story.
CHAIRMAN
ABRAMSON: Dr. Ilowite.
DR.
ILOWITE: I just wanted to point out some
issues that are uniquely pediatric. One
is that children are likely to be on these drugs, if they respond, much longer
than adults, maybe 30-40 years more than similarly affected adults with
analogous conditions, and that any analysis of lymphoma risk to assure safety
for children would, I think, have to be longer than necessary for adults,
whether there's a blip at 600 to 800 days or not.
DR.
WEISS: Can I just ask. Among the slides -- We have one of the
products that is right now approved for JRA, and I believe that we looked, and
none of the cases occur in children with JRA.
I mean, there are some young adults that have developed lymphoma, but no
children. But we have asked -- I don't
know; maybe Amgen can comment. There are
long term registries going on in the JRA population, because it's true, it
might be -- Again, they have less longstanding disease. So that may or may not be a factor.
I
don't even know if there are any natural history type databases with respect to
JRA to try to characterize the lymphoma rates, and I don't know if anybody has
that kind of information, but I would be very interested.
DR.
BURGE: Yes. I was just going to comment. Yes, you are accurate that there have been no
lymphoma cases in pediatric patients, whether in clinical trials or in
post-marketing reports. Again, yes, we
have initiated a registry to continue to monitor safety in kids.
CHAIRMAN
ABRAMSON: Okay. Dr. Siegel, any other clarifications on this
question 2?
DR.
SIEGEL: No, that was a thorough
discussion. Thank you.
CHAIRMAN
ABRAMSON: Thank you. Question 3, Part 1: As part of post-marketing studies, all three
manufacturers have committed to follow between 1000 and 2000 patients with RA
and to provide the agency with updated information on malignancies annually for
a minimum of five years. At five years,
the agency will determine whether additional follow-up will be necessary. The yearly update includes numbers and types
of tumors based on histology and other standard assessments.
Should
the companies be asked to obtain additional specific types of information not
normally assessed in patient management that could help elucidate the
relationship between anti-TNF therapy and lymphoma? What findings would suggest that there be
continued active follow-up of this nature?
I
would just open that up to members of the panel. It does also get to some of the points that
Dr. Gibofsky and Manzi were talking about registries. But let's focus first on the companies'
commitment over the next five years. Dr.
Elashoff?
DR.
ELASHOFF: Well, while studies of 1000 to
2000 patients sound pretty large and, I'm sure, are expensive to do, with
respect to the kinds of rates that we think might be of concern and with
respect to the total numbers of patients being treated with these drugs, those
look rather small.
In
addition, the five-year may be small in terms of detecting some of the kinds of
things that we are concerned about.
CHAIRMAN
ABRAMSON: So additional registries or
patient population cohorts need to be followed in addition to that. Yes?
DR.
WILLIAMS: We are still not going to have
any better idea in five years what the underlying rate is for rheumatoid
arthritis, regardless of stage. I don't think that data is going to get any
better, because nobody will be untreated.
CHAIRMAN
ABRAMSON: Right. Dr. Manzi
DR.
MANZI: I guess I would echo that and
just say that, to me, the only advantage of this over the current system is that
you are now going from passive to more active, and you are defining a certain
set of patients. But you still haven't
gotten away from exactly what people have pointed out: first of all, numbers,
comparator populations, and all of the other confounding issues that I think
much larger registries can help us with.
CHAIRMAN
ABRAMSON: Can we have a clarification as
to how the 1000 to 2000 patients that are being followed have been chosen,
since that is, obviously, just a subset of patients being treated with the
drugs?
DR.
SIEGEL: Generally, the number of 1000 to
1500 and, in some cases, some more is the follow-up of patients who were
recruited into the initial clinical trials for approvals, and then just to
follow those patients along.
There
was no rigorous way of deciding that this was the exact number that should be
followed. So we would be open to suggestions about ways of deciding what the
appropriate number might be.
CHAIRMAN
ABRAMSON: So these are people in Phase
III trials?
DR.
SIEGEL: As these products that were
being developed, we were concerned that adverse events might emerge with longer
durations of exposure. So we have generally advised sponsors to, if possible,
enroll patients -- to roll over patients in all the studies into active drug,
so that at the time of a potential approval, we would have the largest database
that could be had.
So
it's the control trials but also the other trials.
CHAIRMAN
ABRAMSON: Right. Perhaps I would be interested to know from
each of the companies who those 1000 patients are, if they can just in 30
seconds or less describe those cohorts for us.
DR.
BURGE: Yes. The patients in the etanercept long term
follow-up studies are patients from initial, Phase II and Phase III studies and
some additional open-label studies that were early on in the development
program that those patients have rolled over into longer term extension
trials.
In
addition, we have another cohort from the early RA trial that's gone into
open-label extension, and our colleagues at Wyeth have additionally taken the
patients in their early trials in Europe and done the same thing. So those are sort of the early clinical trial
patients that have extended for a long duration.
DR.
FISCHKOFF: In the adalimumab clinical
program, the 1700 patients that I cited before represent every patient who has
ever been in a Phase I, II or III study and has chosen to stay in a long term
continuation.
DR.
DR. SCHAIBLE: Similarly, every patient
in a clinical trial is followed through five years, whether they stay on
REMICADE or not. Then in addition, we
have substantial registries which -- I think you just look at our patients who
are in them right now and who we have planned will probably take us close to
20,000 to 30,000 range of patients prospectively followed.
CHAIRMAN
ABRAMSON: Dr. Gibofsky.
DR.
GIBOFSKY: I defer to Dr. Elashoff with
regard to what extent the number listed here is an appropriate power to get at
the incidence and prevalence of lymphoma in other conditions.
The
other caveat I would offer is, to the extent that the commitment is only for
rheumatoid arthritis, as articulated here, I think we are not going to see the
complete picture. If anything, we should
strongly suggest that this data be collected for all indications for our
patients with Crohn's disease, for ankylosing spondylitis, for JRA and so on,
and not just for rheumatoid arthritis.
CHAIRMAN
ABRAMSON: Dr. Williams?
DR.
WILLIAMS: I have a little concern the
way the patients have been selected. I
have more comfort with the registry that was mentioned by Dr. Schaible. But if we are only taking patients that were
put in the initial studies, those are a selected group of patients that are not
going to be equal to the standard patients that are treated with this drug.
DR.
MAKUCH: I agree with everything. I think that for sample size I couldn't agree
more with Dr. Elashoff. Probably she
could do her calculation, I could do mine, and we all could. But I imagine it would be in the 5000 to 6000
range.
Secondly,
responding to the remark just made about what kind of patients get into this, I
agree that those in the clinical trials are probably very select. So it's been my experience that I have seen
these kinds of studies being done where it is a hybrid. It is composed of both those from the
clinical trial experience to get the longer term follow-up fairly immediately,
as well as putting in perhaps the same number of new subjects into the clinical
trials mix, so that you get perhaps a more general representative group.
The
third thing about this question, I guess is a recommendation, and it came up
with the controls. The control selection
really, I think, requires a lot more thought.
I don't have an answer to it, but I think that, if five years down the
road this were just done, I think we'll all still be looking at one another and
still not know quite what to do. So I
would really give a lot more thought to what the controls would be.
Fourthly,
in addition to SEER, I think it would be -- even next year, to do an update,
from what Dr. Tarone said, to update the analyses using the 2000 data from SEER
that would become available.
Then
finally, if one is doing these kinds of studies, to at least collect the kind
of information that perhaps will allow you to better discriminate among
different possible other explanations for lymphoma: Again, duration, dose, prognostic factors,
concomitant meds, etcetera.
So
I think that this is -- Question number 3 is a good start, but I think it
really needs a lot more work. It's a
very difficult question, in fact.
CHAIRMAN
ABRAMSON: I guess, arguably, some of the
patients who were followed were the very difficult, more severe RAs which would
be of particular interest to follow. Dr.
Schaible and then Dr. Burge.
DR.
SCHAIBLE: Right. I think two things about the registries. First of all, they do, I think, represent a
more real life type of patient than you have in clinical trials, but there is
also this caveat. That is that the
patients who are going to be getting anti-TNF will be more severe than your
comparator population. I can tell you,
we have looked at the patients in our registries, and in both Crohn's disease
as well as RA, you get the more severe patients getting treated with anti-TNF.
You
may need to develop adjustment factors to adequate analyze those data.
DR.
BURGE: The question specifically
addressed the commitment of this 1000 to 2000 patients for five years, but as
we have illustrated in our presentation, we obviously are observing far more
than those patients from our initial clinical trials. RADIUS program has 10,000 patients, 5,000 of
which are initiating etanercept and 5,000 patients who are on other disease
modifying agents.
The
European registries have close to 2000 patients into them now. I think it's around 1600-1700, and continuing
to roll all the patients that go onto TNF inhibitors in those countries.
So
there is a substantially greater effort than just the long term extension
trials mandated by the agency at the time of initial approval. In addition, we have -- again, trying to
understand what the background epi is in RA has been challenging.
Dr.
Silman did a great job of representing his view on the current literature, and
we are trying to explore that further by doing an epidemiologic study in the
Engenics Health Care Program to see if we can shed some more light on this.
So
I think there are great efforts going on to try and help advance this.
CHAIRMAN
ABRAMSON: Dr. Silman, do you want to
make a comment?
DR. SILMAN: Just a brief comment on numbers and
power. Unfortunately, it is not entirely
analogous to a clinical trial, because even if you have control groups who are
not anti-TNF treated, they may have differences.
We
attempted this exercise in the U.K., and we came up with a figure of slightly
under 2,000. About 1900 subjects followed up for five years treated with
anti-TNF would be sufficient to show a doubling in lymphoma risk at five years
compared to background RA risk against an RA untreated comparison group.
CHAIRMAN
ABRAMSON: For our oncologists, would
five years solve the issue of latency and give us some comfort that that was an
adequate amount of time to see an effect of the drug?
DR.
KROOK: I don't really think it
will. I'd like to make two comments, as
long as I answered that question.
One,
pathology -- I mean, the MedWatch which Dr. Cote showed us -- I mean, we've got
473 reports of somehow coding lymphoma, which really only 95 are biopsy
proven. So what are we going to use? The best control that we have are the
clinical trials, and having functioned in oncology clinical trials, my data
managers are bugged all the time, both by industry and cooperative groups, to
are they alive, dead, what's happened, is there anything new event.
I
think that, you know, it would be nice to use MedWatch or a group, but I don't
know how we are ever going to sort it out in that group when we are not -- you
know, to look at all these path slides and then, as Dr. Jaffe said earlier, we
were talking that even the nomenclature in lymphoma is changing and may change
again.
So
I think the best group we have are those clinical trials. Now I'm not sure we are going to get more
than that.
CHAIRMAN
ABRAMSON: Dr. jaffe and Blayney, is five
years enough to give comfort?
DR.
JAFFE: I don't think so. Even if you look at the situation of
post-transplant lymphoma, post-transplant lymphoma is not one disease. It is multiple diseases. Early on, you see the EBV positive
polymorphic B cell lymphomas that can regress spontaneously. Late, you get more monomorphic lymphomas, and
you get even T cell lymphomas and gamma delta T cell lymphomas, and probably
each of those subsets has different pathogenetic factors.
So
I think you need very long term data, and I think you have to really look at
the cases, because lymphoma is not one disease.
I mean, we are talking as though lymphoma is one disease. It is multiple diseases, and you don't know
-- You have to sort out what is due to disease, again what is due to treatment,
and what is due to background noise.
DR.
BLAYNEY: I would certainly defer to Dr.
Jaffe on that point. I don't think we
know. There are, as she says, many
different diseases, but it is worth pointing out that lymphoma is, as an
oncologist, one of the diseases which we do quite well at. Even if we don't get rid of the
immunosuppression, we do put into remission a fair number of these patients.
So
again, it is quite different from the secondary leukemias that are seen and
secondary lung cancers that are seen after radiation. So bearing in mind that the risk of death
from lymphoma is not 100 percent.
CHAIRMAN
ABRAMSON: Dr. Elashoff.
DR.
ELASHOFF: I just wanted to make a
comment about the value of the registries.
We saw some figures for one registry about eight percent attrition per
year. Registries are only really
valuable if the patients that you get into them stay in them for long enough so
that you really have long term data on each patient.
If
you get a lot of patients in and then they are lost to follow-up after six
months, then you never get much more than six months information on people, no
matter how many patients are in. So the
whole issue of keeping the attrition rate low is extremely important to the
potential value of any registries.
CHAIRMAN
ABRAMSON: Dr. Manzi.
DR.
MANZI: I think I would just like to make
-- I agree with you about attrition, but I also think it takes a tremendous
amount of support, financial support, to keep these registries intact for long
periods of time.
I
credit Dr. Wolfe and other people who have tried to do this, but it takes a
commitment on whoever is going to support it to have the staff available to get
all the lost to follow-ups and accuracy in biopsy reports and everything that
we are talking about that is critically important. I think, to their credit, they are doing
probably a lot of this without the full support that it takes to do it.
DR.
COTE: I'd like to concur with my
colleagues who are also reticent to cut things off a priori at five years. I
think there's some wisdom in that, because other information from transplants,
to AIDS, to atom bombs have all shown that there are very late term effects.
I
think therein will lie the real answer, is in long term cohort studies, but I'd
like to bring the committee back for just a moment to this, the MedWatch
program, the 158 cases of lymphoma that we know that do exist and for which we
have very poor information.
What
kinds of information shall we -- Is the juice worth the squeeze to go back and
get the kinds of histology information, perhaps secure blocks and slides,
perhaps do testing for EBV, perhaps find out those kinds of questions that were
brought up earlier in the day in terms of latency, between times of treatment
that were begun and times of development of lymphoma? Is it worth mounting an effort to do that or
requesting sponsors to do that at this time?
CHAIRMAN
ABRAMSON: Before we address that, Dr.
Williams had a comment. Then we will
come back to that.
DR.
WILLIAMS: We hear talk about comparator
groups and control groups, and there won't be any. We are much more aggressive in our treatment
of rheumatoid arthritis, and these are the best agents we have. So anyone who doesn't respond fairly
dramatically to other agents are going to end up on these agents. So there really aren't going to be a good
control group.
DR.
KROOK: It's going to be historical, if
any.
DR.
WILLIAMS: We've heard the historical,
and it hasn't been adequate for us today.
CHAIRMAN
ABRAMSON: Right. I think just my own response to the question
is the MedWatch is a good way to maybe pick up a signal, but probably not a
good place to go looking, digging for more data, since we have, in my own view,
more sophisticated ways to do that.
I
wonder, you know, between the Tennessee Medicaid database, this ARAMIS --
there's so many large clinical population medical care databases now, and I ask
Dr. Siegel or a representative from the FDA, how is the FDA using these large
population medical care databases to capture this information?
DR.
BRAUN: We had a Request for Proposal
that went out somewhere around a year ago at the FDA, and we are contracting
with the UnitedHealthcare which is a nationwide medical care reimbursement
insurance organization, and using its claims database, we are going to try to
look at some of these questions, these adverse events that have been discussed
today.
Roughly
-- This is very rough -- there is around 4 million covered lives, but it is
very instructive when you get into these databases and look at the number of
patients who are taking the biologic agents for rheumatoid arthritis. They become very small. It's amazing how you can start with 4 million
covered lives, and you find 1000 or 2000 patients who are taking -- who are on
etanercept or on infliximab.
You
know, the adalimumab has not hit the really -- hit those kind of databases
yet. So that is really a blank. It's very challenging, and as was mentioned,
it is also expensive, certainly for us, because we don't have a large research
budget. But we are trying to obtain
independent data, as was mentioned, real world use of the products.
We
have already -- I think we are confident that we will be able to demonstrate
some results, but we won't be able to easily, if at all, answer these kind of
questions, say, about can we demonstrate an increased risk of lymphoma or not
definitively in patients on biologic agents versus some comparator, say, a
methotrexate treated group.
This
is an ongoing project that we have, and it is something that we can try to
obtain independent information from.
CHAIRMAN
ABRAMSON: Dr. Blayney.
DR.
BLAYNEY: I think the insights are going
to be on a biologic level. As was
pointed out, both by our pediatric colleague and Dr. Williams, people are going
to get this medicine earlier in the course of the illness and, hopefully,
improve morbidity, but that also gives them a longer chance to develop some of
these untoward side effects.
I
think that the juice is going to be on a biologic level and find out either who
is at risk for these and how to treat them.
We are not going to have a control group. I think the work of epidemiology is done. It now needs to move to the laboratory and
our bench colleagues.
CHAIRMAN
ABRAMSON: Dr. Williams, then Dr. Burge.
DR.
WILLIAMS: Involving the question of
juice and squeeze, I think that if what we are seeing is that the lag time is
600 to 800 days, we probably won't learn anything, and we'll come back with
SIRs of 5, and we won't know anymore than we know now. However, if we are seeing the beginning of a
group of patients that will develop lymphoma as a result of these therapies,
then we may see higher results, and I think it is still worth looking at it so
that we are not missing something bigger.
DR.
BURGE: I just wanted to respond to Dr.
Cote in that what's the value? You know,
is there value in going after this? Our
personal bias is that, certainly, more information is better, and there's multiple avenues by which you can get data,
clinical trials certainly, registries certainly, doing some work with
epidemiologic work.
We
actually feel it is also hugely valuable to try and pursue and get as much
information as we can on these cases in post-marketing. We developed a standardized worksheet to go
after specific issues on things like lymphoma, and we have been very successful
at it.
We
have obtained 70 percent of the histopathology reports. Again, that's not 100
percent, but certainly having more data is much more helpful in interpreting
the situation than having less, and then when you can put all these pieces of
the puzzle together, the clinical trials and the registries and your data from
your post-marketing, we get a much more complete picture.
So
we think that it is not only useful, but it i s feasible to pursue, and again
we are not going to get 100 percent of it, but it is very helpful.
CHAIRMAN
ABRAMSON: Thank you. So the question, just to go back to the
question: The companies are already
following 1000 to 2000 patients and have registries of various kinds. Should the companies be asked to obtain
additional specific types of information than what is already being collected?
I
wonder if there is a comment from the committee?
DR.
WILLIAMS: Again, we have already mentioned
this, but all these patients come from trials, and I think the registry done by
Centocor is going to probably give us more information. We need to get some patients who are not
selected for the early trials.
CHAIRMAN
ABRAMSON: Dr. Weiss.
DR.
WEISS: Though it sounds like from the
comments that came out as part of these discussions, there's certain things
that maybe it will be difficult to do in the post-marketing passive system, but
to try to be a little bit more proactive in terms of things like the EBV
association, things that there might be a window of opportunity to try to
collect, or it's better to collect it up front than to try to go back maybe and
hunt up this information.
So
I'm just wondering about with this ongoing -- you know, either the registries
or these long term extension studies, to go back and look and make sure that
there is active case report forms that actually specifically have places to try
to fill in the blanks with respect to things.
And there generally are, but for things like concomitant medications or
duration of treatment, but other things that are more difficult maybe like
other concomitant medications, prior medical -- prior types of treatments, the
EBV in particular, which may or may not always be collected.
I just want to know if the committee
thinks it would be good to just sort of relook at what is being collected now
in either these registries or these extension studies that are going on, to
just try to make sure that we get the biggest bang for the buck with those
data.
CHAIRMAN
ABRAMSON: I take it at this point,
there's not been any standardization of the various registries by the FDA at
this point. Is that correct?
DR.
WEISS: The FDA isn't really -- you know,
isn't running them, and we ask the companies to collect information and then,
as you see, they have all gone on beyond just these open label extensions and
developed registries of different kinds.
I
mean, we haven't looked specifically to make sure that every case report form
or every type of questionnaire is exactly the same. We certainly have highlighted that we are
particularly interested in infections and malignancies and lymphomas, and
that's been sort of the standard kind of theme throughout all of these.
CHAIRMAN
ABRAMSON: Dr. Ilowite.
DR.
ILOWITE: Having worked with one or two
of the registries, one of the problems with the registries is that, if they
start a different biologic treatment, they are automatically kicked out of the
registry, at least in the one I've been involved in.
Of
course, that's just the kind of information we don't want to lose, someone who
has been exposed to a series of biologic agents. So it would be nice to have cooperation among
-- and coordination among the various registries.
DR.
GIBOFSKY: I think that's an important
point, Dr. Abramson, that you began and that Dr. Ilowite followed up on. That
is, while ideally it would be nice to have one registry as per Dr. Silman told
us. The reality is there are half a
dozen of them or so, and to what extent we can strongly urge that there be
common data collection by whatever format is being used for that collection,
but common data collection of a common dataset that can be mined across
studies, I think that would go a long way toward answering many of the questions
that we have.
CHAIRMAN
ABRAMSON: This could be a good role for
the ACR, some professional organization to develop a collaborative effort with
these outcomes.
DR.
GIBOFSKY: If Dr. O'Dell is still in the
room, perhaps he would like to speak to his experience in trying to get that
project going. Or not.
DR.
WOLFE: Actually, Dr. O'Dell did try to
get it going, and it was the NIH that expressed disinterest in projects that
were not hypothesis driven, and that's what really killed it. So everybody should know that, I think.
If
you want to really know how to do it, you need to ask Dr. Silman who is doing
it -- who is enrolling all patients and doing it really correctly, because he
has -- The nature of the support he had and the nature of the government
support is such that that's the way to do a study.
Now
speaking for registries, the national databank that I run is not a REMICADE
registry. It's a databank of all
patients with rheumatic diseases, and we take them all, whether they are on drugs
or not, and we continue them, and we follow them, and we get all medications,
and we try to follow them over time.
I
think one of the things that I think isn't clear from here is that what really
is needed to collect. My experience with
this is that the target moves. When the
drugs first came out, no one quite knew that there was a tuberculosis, and two
years went by before suddenly everybody wanted to know about tuberculosis, and
then congestive heart failure came up last year.
It
would be very helpful, I think, if there were some sort of a conference for
database managers to try to understand how best to collect it and what needs to
be collected as a very minimum.
Having
said all of that, it is extraordinarily difficult to get this information,
because you have -- Up to now, you have had -- You need patient consents for
every single thing. Beginning April 1,
the world is going to change, and if you think that it's difficult now, it is
going to be very, very difficult to get this sort of information.
I
think it is because no one has really quite understood the need for it or
defined the need for it that has really made it hard; and if we all got
together and perhaps defined what we want to collect, that would help a great
deal.
CHAIRMAN
ABRAMSON: Dr. Weiss, any further
information on this question?
DR.
WEISS: Dr. Anderson.
CHAIRMAN
ABRAMSON: Dr. Anderson, one comment.
DR.
ANDERSON; I'd just like to make a
comment. I think that the work that Dr.
Wolfe has been doing is just admirable in setting up his data bank, but in
addition, I think that, in addition to all the clinical information, you really
need in these databanks information of a more health services type.
I
would hope you wouldn't have to have too much of it, but just to know -- You
know, the reasons for starting and stopping drugs aren't all clinical, and some
of them have to do with whether the patient can pay for the drug or not or
whether there are reimbursement
mechanisms available to them for paying for the drugs. So that these factors may have quite
substantial effects on drug choices and, I think, should be considered in the
analyses.
MS.
McBRAIR: As a consumer rep, I think this
would be extremely valuable data, and people with rheumatoid arthritis would be
very grateful to have information that would be collected on them as people
that have a very serious disease. I
think Dr. Anderson's comment about the additional information to be collected
is also important.
Rheumatoid
arthritis has had its first focus because of these new biologics. It really wasn't studied very much as far as
-- or didn't have a lot of answers to help people. So I think this has been absolutely wonderful
that there are some biologics medications that can help.
I
think we need to learn more, and a national database would certainly provide us
with some wonderful information that would be helpful to all of us.
CHAIRMAN
ABRAMSON: Before we move to the next
question, I think a historical note is important, because you always want more
data, but I think both the FDA and the companies need to be commended; because
I remember in 1998 we were worried that there wouldn't be follow-up and
databases, and the FDA mandated. I think
the companies even went beyond what was mandated, and we have a lot of
information and a lot of new insights into this disease, even separate from
this particular toxicity, that came as a result of this interaction.
So
I think that's just a historical note from someone who was here five years ago.
Let's
get to question number 5: Please discuss
how best to communicate information about lymphomas to health care providers
and patients. For each of the respective
product labels, please discuss how the agency should present the data on the
observed incidence of lymphoma, the degree to which the data suggest an
association, and the degree of uncertainty about the association. Should the standardized incidence ratio with
respect to the general population be presented?
Should the SIR with respect to the RA population be presented? Should labels be similar for each product?
Before
we tackle that specifically, Dr. Siegel, can you just briefly give us -- remind
us what the specific labels are right now?
Remember, the HUMIRA label was fairly explicitly discussed, but to address
this question it would be nice to know.
DR.
WEISS: Well, we handed out -- We don't
have an overhead or a slide of this, probably because it is so difficult to
do. We handed out copies of the label.
I
want to make a comment, that I hope you appreciate the difficulty of getting
the entire label on one page, front and back, on a very large piece of paper,
but we managed to do that. It took some
time and maneuvering. So I hope you appreciate that, so you don't have stacks
of paper to look through.
We
have wording -- Actually, Abbott provided the wording -- the label for HUMIRA
in their packet. I want to point out
that that's the one -- because it's the newest information and because we had,
adding onto the HUMIRA experience, the experience with infliximab, and with
etanercept, to some extent, in our background, we had more information in the
HUMIRA label with respect to malignancy and lymphoma than we have in the other
labels currently. But that is one type
of question that we want to put to the committee, and we certainly talked to
both Centocor and to Amgen about ways to update the label.
Everybody
has been receptive to it. It's just a
matter of trying to find the right balance.
I don't know if would help to read what we have, if you want me to do
that, so that the audience can hear it.
I know the committee -- It is very small print, but we provided
information in the warning section for the HUMIRA label on malignancies.
It
says: "Lymphomas have been observed
in patients treated with TNF blocking agents, including HUMIRA. In clinical trials, patients treated with
HUMIRA had a higher incidence of lymphoma than the expected rate in the general
population." Then it refers to the
adverse reactions.
"While
patients with rheumatoid arthritis, particularly those with highly active
disease, may be at higher risk, up to severalfold, for the development of
lymphoma, the role of TNF blockers in the development of malignancy is not
known."
Then
we also have a section -- If you go to the adverse reactions section, we have a
little bit longer description in the adverse reactions section, actually more
on the data.
We
say in the adverse reactions under a section called "Malignancies: Among 2,468 RA patients treated in clinical
trials with HUMIRA for a median of 24 months, 48 malignancies of various types
were observed, including 10 patients with lymphoma. The SIR for malignancies was 1.0," --
and we give the confidence intervals -- "and for lymphomas was 5.4"
-- and we give the confidence intervals.
"An increase of up to sevenfold in the rate of lymphomas has been
reported in the RA patient population, and may be further increased in patients
with more severe disease activity. See
Warnings."
Then
we describe some of the other types of malignancies that were seen in the
HUMIRA database. Severalfold -- that is
up there. Thank you, Abbott.
CHAIRMAN
ABRAMSON: So let me just reframe, if I
may, this question, which is that, in two parts, how best to communicate this
information, and then in essence, should the label pretty much for the other
drugs be comparable to this? I think, if
somebody would like to open the discussion -- Dr. Day has particular expertise
in this area. I'd like to begin with
her.
DR.
DAY: I'd like to comment that, if there
is the decision to go with one of the ways to represent the data, the SIR or
something else, then it would be useful to have it be the same across all.
Although a highly trained and specialized physician may know how to use all of
them, it makes it very difficult to compare across labels when there's
different forms of representation.
This
question is basically a three by three.
We have the three products by the three ways to represent information,
and we have to consider what the nature of the data are in each case and
whether specific information should or should not be provided. Once that is done, if we could agree that
there is an appropriate way to represent the information, that would move us
along quite a bit, but I would speak very strongly for the same method or
format of presentation of the information across labelings for these comparable
drugs, especially since the same physicians will be looking at all of them.
CHAIRMAN
ABRAMSON: So let's stick with that part
of the question. Does anyone else want
to address whether these labels should be different from the HUMIRA? That's one aspect of this. Dr. Williams?
DR.
WILLIAMS: I don't think they should be
different. I think they should be the
same, and I thought that the statement under the warnings was applicable to all
three.
When
you get under adverse events, it was specific to adalimumab, but under warnings
could have been to all three.
CHAIRMAN
ABRAMSON: Anyone disagree with Dr.
Williams?
DR.
DAY: May I ask a question? I notice that there are boxed warnings for
two out of the three, and if this -- We always have to decide not only what is
the information but where shall it go.
CHAIRMAN
ABRAMSON: Right. So the boxed warning pertained to
tuberculosis. Is that what you mean?
DR.
DAY: Right. But if we should decide that this should be
in a boxed warning, there would be implications -- as opposed to the warning
section.
DR.
WILLIAMS: I would argue against the
boxed warning on the data that we have right now. I think what is stated there is enough to
state that there is a concern, but we don't know anymore about it than what's
--
DR.
DAY: And I would agree with that. I'm just trying to focus in.
DR.
SIEGEL: I'd like to thank the
panel. It was a very helpful discussion. I just wanted to maybe provide a little
history and just raise one concern.
We
mentioned that, when we craft language for labels, that we do it based on the
data we have, and the datasets for the first two approved TNF blocking agents
was more modest, and we couldn't make as many conclusions or as many
calculations.
With
the database that was available for adalimumab at the time of its approval, we
had much more information. We could
calculate an SIR with reasonable confidence intervals, and face the question of
what to do with it.
We
thought that the kind of wording that was used in the previous labels probably
clearly didn't contain all the information that we had for adalimumab, and we
crafted the language for adalimumab based on this additional information.
Now
having gone back with the other products to collect this information, we need
to make a decision about how those labels should be done, and I think the
committee has given us good advice on that.
I
do want to bring up one issue here, which is that one of the confounding
variables is the activity and the duration of disease, and there is some
thought that these factors may substantially impact the background rate of
lymphomas.
Some
people have raised a concern about a hypothetical company developing a new
product who selectively studies their product only in very early disease or
people with mild disease, who might end up with a lower SIR potentially based
on recruiting patients with less active disease and then being at some kind of
-- in a different situation when it came to incorporating that language in the
label.
Is
there additional information that we should include in the label -- for
instance, the average disease activity or the median disease activity in terms
of, for instance, acute phase reactants at the time of beginning the product,
the duration of disease before bringing in the product, anything like that that
would be helpful to provide a common metric?
CHAIRMAN
ABRAMSON: As a physician who tries to
read these labels from time to time, the less you put in, the better, if it
doesn't really add that much value. I
think -- Not to be facetious, I think since we don't know for sure what that
information means yet, probably the simpler, the better for the physician being
able to digest what is going on.
DR.
WILLIAMS: Also, the milder the disease,
the harder they are going to be able to show disease modification, too.
DR.
BURGE: Hello. I was just going to say, again, we do have a
substantial database. Again, I know
everybody would like to have an enormous, 30 million patient years of exposure,
but we have a substantial clinical database.
It is continuing to grow. We've
got five to six years of clinical experience, four and a half years of
commercial experience, and we do believe it is very important to communicate
the data that we have in our package label, and we proposed a label addition in
the fall of last year.
I'm
sure that a lot of this -- We've been discussing this with the agency, and a
lot of it was awaiting this discussion we would have here. It is certainly our position that we believe
that products should be individually assessed, and they should be assessed on
their data and, when discussing the appropriateness of the label, should
reflect the data.
We
personally, with our SIR in the 2 to 3 range, don't believe that the data from
the etanercept experience elevates it to a warning in the label, and would just
like to make that statement. But we do
believe it is very important to communicate this, and we are in this active
negotiation and discussion with the agency to move this forward.
DR.
LEFKOWITH: I wonder if I could
comment. I wanted to follow up on Dr.
Siegel's questions and comments that we have heard from Doctors Makuch and
Tarone.
I
think it is fair to put into the label the data that are derived from the
clinical trials. The issue, however, is
whether or not all SIRs are created equal, if you will.
I
believe that, given the range of SIRs that are possible within the RA population,
from one to 26-fold, small changes in trial population may make an enormous
difference. Whereas, it may be
informative to portray the SIR within the label, merely indicating the lack of
-- without appropriate context, it may be hard to compare the rates, and
physicians may make wrong comparisons.
I
believe there is precedence within labels to state specifically that, that
rates derived within different products in different trials cannot be directly compared. I think that is more informative to physicians
than simply stating a rate and stating that it means something, and having them
draw inappropriate conclusions.
DR.
VOSE: My name is Julie Vose. I am a lymphoma specialist from the
University of Nebraska Medical Center, and I would just like to comment on the
SIR.
I
am usually on the receiving end of things that go on after patients have
received different products in patients that have RA, but I think in patients
that have RA, we know that there is a background rate that's there, and the oncology
literature would say between 2 to 2.5, and that's very consistent with what
we've heard today.
I
think it is very important for us when we are treating our patients to look at
the products that we are trying to compare, and the SIR is a very good way to
do that across products, but also to keep in mind that we need to know what the
background rate in RA patients is n that context, and also to the extent that
the patients have with respect to their disease status, and certainly the more
severe patients would have a worse set disease and SIR.
So
we need to keep that in mind. And I
would be in favor of putting that in the label, but the data that we have is
not conclusive that that is necessarily a causational. So I think I would be against putting it in a
warning box per se. Thank you.
DR.
SCHAIBLE: I would just mention there is
some precedence here in how immunogenicity is labeled, and that there is
statement in labeling on immunogenicity rates that these rates cannot be
compared from one product to another because of a number of confounding
factors, which I think we also have here in terms of the nature of the
population studied and the fact that one or two lymphomas could make a huge
difference in the estimate of the SIR.
DR.
GIBOFSKY: Mr. Chairman.
CHAIRMAN
ABRAMSON: Yes.
DR.
GIBOFSKY: I think, as important as it is
to determine what we put where in the label, I would hope we don't lose sight
of the fact the question asked is how best to communicate, and if the label is going to be the only place that
we put it, we are missing a wonderful opportunity to get information out to the
physicians and to our public.
I
think we should be thinking in terms of rapid communication such as the ACR
hotline, sister publications with the AGA, and primary care specialties who
take care of our patients, communications through our patient representative
organizations like the Arthritis Foundation and the Crohn's and Colitis
Foundation we heard from today.
I
think the label is one important place, but we should not spend an inordinate
amount of time trying to put 2 point font into 5 point boxes and miss the
opportunity to give the bigger message.
CHAIRMAN
ABRAMSON: Okay. So just to follow up on Dr. Gibofsky's point,
we should go to follow up the discussion how best to communicate. But before we move to that, I'm wondering if
the FDA has any comments about the specific issue of the label from more
opinion from the committee at this point?
DR.
WEISS; No. I think that we heard some very good advice. We struggle a lot with coming to labels and
to updates on labels all the time.
Agree, it's not the only or perhaps not even the best way of
communication. It is has what the FDA
has jurisdiction and control over. A lot
of the other methodologies that were described are very, very good, but not
ones that we mandate or have any particular say-so in, other than, you know,
the label and Dear Health Care Provider letters as our main ways of trying to
communicate, as well as things like any publications that have been done in
this area and presentations. But the
issue of whether or not there's identical label for similar products or
different, and we try to explain, for instance, with the tuberculosis and
infections, there are some differences based on the data that we saw, but there
are other times, perhaps this being one of them, where the data may be
different but may not be, because of some of the uncertainties and immaturity.
You
know, again it's not an easy question, struggling to be fair and balanced with
presenting the data. That's basically a
comment I wanted to make. But I very
much appreciate the discussions and advice we have received thus far.
CHAIRMAN
ABRAMSON: Yes, Dr. Anderson?
DR.
ANDERSON: Yes. I appreciate that there's not much room on
this label to put anything extra. But it
would be -- and maybe these other avenues of communication would be the place
for this. But I think it's not enough
just to have SIRs. I think you need the
absolute risk, you know, the excess risk, because an SIR can be misleading to
people who don't appreciate just how low the baseline risk is.
So
when other means of communication are used, then I think both ways of
describing the risks should be included.
DR.
TARONE: I'd just like to reiterate a comment
I made in my presentation. I'm not
really sure exactly what has been decided about what to put in the label, but I
want to make the point again that, from a statistical point of view, there is
no difference between the SIRs that have been reported.
Quite
frankly, given the severity of the rheumatoid arthritis in the clinical trials
for adalimumab, I would have been stunned to see an SIR of 2.3. I would have been stunned. It's not consistent with what is known about
patients with serious RA disease.
These
SIRs are not significantly different. I
don't know how you can put them in without having some indication of the
variation. Again, I don't think
confidence intervals are well understood.
It's a serious issue.
I
think the most serious issue is how you get across the fact that there is
variation in these estimates that you expect to see, and they are not
comparable just from a statistical point of view. There is no significant difference.
So
it will be misleading, I think, to put in the individual SIRs and just have
them there for people to see.
CHAIRMAN
ABRAMSON: I would think that is also the
sense of the committee, that if the SIRs are included, there has to be a very
clear statement that there is no way that one can compare one agent with
another based on these numbers, and that more information is really required.
DR.
WILLIAMS: In fact, my recommendation was
they use the warning statement which was very generic and did not have SIRs in
it, because it stated there was a risk and we didn't understand what the risk
was.
DR.
WEISS: Just to comment generally. In the hierarchy or the labeling rules, we
generally put in information in a more descriptive term like you saw in the
warning statement, and then usually specific data in the adverse
reactions. That's generally sort of how
the labels are set up. So that's sort of
the reason why you saw the format that you did for the HUMIRA label.
CHAIRMAN
ABRAMSON: Okay. So just to finish this segment and to pick up
on what Dr. Gibofsky had started, what is the best way to communicate this
information? Are there other suggestions
in addition to what Allan raised? Yes?
MS.
McBRAIR: This isn't exactly a
suggestion, but I think it is important not to scare patients. People with rheumatoid arthritis have been
forever grateful for these medications, and I don't think anything that we've
heard today is going to keep them from these.
They have been wonderful.
So
we just don't want to scare them either.
They need to be vigilant. The physicians
need to be vigilant. The patients need
to be educated on how to be vigilant, and that seems to be the most important
piece here for me.
DR.
KROOK: Just a comment. As was said before, that most of the people
who are getting these drugs are taking care of by sub-specialists. Somebody said 90 percent. So whenever, at last in my specialty, you sit
down and say the side effects and the whatever, I think we depend on the
physician, and if these are mostly all rheumatologists, then it's through their
societies and through whatever that this would be done.
I
think I heard 90 or 92 percent were prescribed by rheumatologists. So those are the people that should be to.
DR.
BLAYNEY: I think the other comment to
make about the label, and it may be obvious, but that's what the people -- the
sales force who calls on me uses. I
would -- Any difference is going to be brought to my attention, regardless of
how carefully I read the label.
CHAIRMAN
ABRAMSON: So the best way to educate
doctors is to make one better than the other.
Dr. Siegel.
DR.
SIEGEL: The other part of question 5 was
whether the SIR, with respect to the general population, should be used. And then whether the SIR, with respect to the
RA population, should be presented.
I
wonder if we could get some specific comment on that. If it should, what would you use as the
expected rate in the RA population?
Would you use 2.2, and what about varying rates with different levels of
disease?
I
understand the difficulties, but it would be helpful to have some comment.
CHAIRMAN
ABRAMSON: I think it's important. I think everyone would agree that it is
important that the RA SIRs be in there, and that the range for severe disease
be noted, can be at this level and even higher, because that is the only
context that this information can be dealt with, I think. I don't if people have different comments on
that.
DR.
DAY: I'm wondering if the people who are
concerned about providing the SIR have more comfort in thinking about having
them provided for both the general population and the RA population. Would that not ameliorate their concerns?
DR.
ELASHOFF: I'm not quite sure I
understand. Are you talking about saying
the SIR as observed in these trials and the SIR for RA compared to the general
population from prior epidemiology data, or are you talking about letting
people divide the one by the other, which I would be strongly opposed to?
DR.
SIEGEL: One possibility -- and it would
be very difficult to calculate and very problematic -- would be to say
"the appropriate comparator for calculating an SIR would be a comparable
patient population, namely a rheumatoid arthritis patient
population."
To
do that, you need to have an estimate of what you would expect the rate would
be in that patient population, and you could calculate an SIR based on those
assumptions. If it was twofold higher,
say, than the general population and you calculated that the RA population was
twofold higher, you would call that SIR 1 perhaps.
That
would, of course, be very problematic, because it depends on what you choose as
the SIR for rheumatoid arthritis compared to the general population. So that is really what we are asking, if you
are comfortable with the way the HUMIRA label, for example, is currently
expressed or if you think it should be done in relation to the RA population.
DR.
WILLIAMS: I personally think using SIR
is going to be more confusing than it is going to be helpful to the average
physician or person that reads the label.
DR.
DAY: What would you recommend instead?
DR.
WILLIAMS: I don't know, but I had to
educate myself on this for this panel, and I didn't know about SIRs before we
got into this panel, and I'm just thinking that there are so many areas that we
have discussed and so many variations that you are going to end up with quite a
long statement if you have to explain the SIR in the normal population and the
SIR in the rheumatoid population and the SIR in the patients who have had
lymphoma.
CHAIRMAN
ABRAMSON: Currently, in your label for
HUMIRA you do say that the RA SIR is higher than the normal population. You cite a reference, and that may be
sufficient. Dr. Boscia.
DR.
BOSCIA: Dr. Abramson, I'm going to go out on a limb a little bit here. I'm going to get a little provocative. I'm outside my area of expertise, because I'm
an infectious diseases trained physician, but this committee is very familiar
with NSAIDs and Cox 2 inhibitors. I mean,
you deal with them all the time. You've
dealt with them in the past.
It's
my understanding that for NSAIDs and then even when the Cox 2 inhibitors became
available, that the incidence of GI bleeds has basically been registered as a
range for the different products, and it's done that way, I think, partly to
prevent one competitor from differentiating themselves from another competitor
based on noncomparative data.
I
think it's been pretty much agreed that, in order for a competitor like a Cox 2
inhibitor to be able to differentiate itself from an NSAID in GI bleeds,
they've got to do a very large comparative trial or some sort of trial to show
that difference.
So
because we don't have comparator data in comparative trials, and because the
populations have been so different in the trials in some instances -- and that
was one of the reasons why I put up our early RA study versus our DMARD
resistant study, because there were no lymphomas in early RA and there were
four lymphomas in DMARD resistant RA.
I'm
just wondering if -- I said I was going to be provocative -- if it would make
the most sense to list a range for the different competitors. I just thought I would mention it.
CHAIRMAN
ABRAMSON: I think, in the case of the
NSAIDs, they all have the class statement that they may all cause GI toxicity,
and I'm not sure that that's necessarily -- that that statement should make a
better range is pertinent to this discussion.
Dr.
Paulus.
DR.
PAULUS: I'm Hal Paulus. I'd rather not see any SIRs in the label or
risk ratios, particularly for these rare events. If I'm a patient, I don't want to know if I'm
twice or ten times more likely to get something than somebody else, if I don't
know what the likelihood is that somebody else is going to get something.
So
what you would like to know is, if I start this drug, what's the chance that
I'm going to get a lymphoma. You can say
that for the general population the chance of developing a lymphoma at sometime
in their life is one out of 1000 or one out of 10,000, and for patients with
rheumatoid arthritis it's one out of 500, and with this drug it's in the range
of the RA population or whatever range it is.
Then
the patient can say, well, I'd take a chance of one out of 500, because I think
this stuff works. But if you tell them
that the SIR is 5.6, they don't have the foggiest idea what it means, and the
doctor doesn't know either.
DR.
GORE: My name is Jeff Gore. I work at Wile Medical College of Cornell
University in New York, and I was a member of the steering committee for
RENAISSANCE, and I look at -- I evaluate drugs from time to time.
I'd
like to make an observation here that may be worth thinking about. You all know this, but I'd like to state it
anyway, and it's a follow-on to something Dr. Boscia said a few minutes ago.
He
pointed out that the populations that are studied with the different agents are
different and, therefore, it is hard to compare them and lump them together
when you talk about writing a label.
I
think another point has to be made, and Dr. Siegel made it earlier, but I want
to state it in a different way. When you
have substantially different molecules, two substantially different molecules,
and they happen to share one pharmacological effect, if you think of it that
way -- in this case, doing something to block the effect of TNF alpha -- when
they share one pharmacological effect, it doesn't mean that they share any
other pharmacological effect.
In
fact, all drugs have multiple pharmacologic effects, and we don't even know all
of them. The clinical effects are the
net of the pharmacological effects. If
we don't know the pharmacological effects, it's hard to trace a given
pharmacological effect to a clinical effect.
Knowing
that, the FDA always asks for data. They
do a body count, and that's what's been done here. I think the suggestion would be that it would
be useful to do what the committee seems to be doing, which is to say we don't
have all that much information here. We
have some suggestive or tantalizing suggestions, suggestive data, but nothing
that really hits the mark to allow us to confirm or prove something with
reasonable certainty and, therefore, we want more data.
Rather
than lumping together the data from drugs that have been studied in different
populations and have multiple pharmacologic effects, of which they perhaps share
one, and maybe they share more than one, maybe it's better to get more
data.
So
I just offer that as an observation.
CHAIRMAN
ABRAMSON: In view of the time, let me go
back to Dr. Siegel. In terms of this
question of labeling, is there anything -- Obviously, there is some complicate
issues to be addressed. Is there any
final comment you would like to make on this?
DR.
SIEGEL: No. We really appreciate the committee's
advice. I think we've gotten the
information we need from you.
DR.
WEISS: I think we got a good range of
suggestions, and I think we are going to take that back home and reconsider
things, but we have a lot of good material to work with.
CHAIRMAN
ABRAMSON: Okay, thank you. We are going to take a break in one minute,
but I think, if we looked at question number 6:
Please comment on the incidence and types of other malignancies observed
in the TNF blocking agents. Do these
data raise any concerns at the present time?
The
sense is not, and we can deal with that question that way.
Okay,
why don't we take a ten-minute break and come back to do the last question at
about 4:20.
(Whereupon,
the foregoing matter went off the record at 4:13 p.m. and went back on the
record at 4:31 p.m.)
CHAIRMAN
ABRAMSON: We are going to go to the
final two questions, and as people are taking their seats, I will read question
number one.
Please
comment on the data observed in the randomized controlled trials in patients
with New York Heart Association class III and IV heart failure as well as the
spontaneous reports of adverse cardiac events in patients with RA. Is it reasonable to discuss CHF related
safety concerns in labels for all TNF blocking agents? Other than product label changes that will
caution use in patients with preexisting CHF or who develop CHF while on treatment, should the companies
be asked to develop additional procedures for congestive heart failure risk
management?
I'll
open that up to members of the committee.
Yes, Dr. Makuch?
DR.
MAKUCH: Yes. This was an interesting situation. I'm looking at the FDA comment that says
there were deleterious effects of infliximab in the CHF patients and that in
etanercept there were concerning trends in CHF patients.
So
two comments. One is that there does
appear to be a discrepancy in opinion or difference between the two drugs with
respect to the effect on CHF.
Secondly,
even within Enbrel itself, there is a discrepancy of results within the two
trials. Again, I wanted to focus a
little bit more on the futility aspects of those two trials, because I'm trying
to understand both this between drug as well as within drug distinctions
occurring.
So
I was hoping that, one, there would be a further clarification of the futility
rule and its relationship, if any, to safety in CHF in particular, and
secondly, just to know more about the safety data at the time the trials were
stopped.
CHAIRMAN
ABRAMSON: I understand Dr. Packer is a
consultant with Centocor today, and he was a principal investigator on these
studies. Dr. Packer, would you mind
coming to the microphone and addressing some of these questions, please?
DR.
PACKER: My name is Milton Packer. I'm from Columbia University. I guess I sort of hold myself responsible for
some of these issues, since I was the senior author on the first paper to ever
report that TNF was elevated in heart failure.
It might be a therapeutic target.
So
a lot of the enthusiasm that pharmaceutical companies had for blocking TNF
which has not paid off in the area of heart failure, I guess our initial paper
sort of led them astray.
I
also, I guess, have the dubious hat of having been the co-principal
investigator for the heart failure trials for both sponsors and, although I am
here today as a consultant for Centocor, I guess I can discuss any information
which is publicly available on either trial or from the heart failure
perspective.
CHAIRMAN
ABRAMSON: Dr. Makuch, do you want to
address one of your questions to Dr. Packer in terms of the methodology?
DR.
MAKUCH: Well, I guess it was just to
explain more about the futility index. I
mean, in particular, as mentioned earlier, there is sort of a one-sided
hypothesis to this, just looking at the efficacy component, and there was not
the other side of the coin where one would also be simultaneously looking at a
safety issue.
Of
course, if you stop the study because you are only seeing a lack of efficacy,
but you are sort of going down the safety concern side, but you stop only
because you have the efficacy issue at heart, well then, almost by definition
you are not going to see a safety issue, not because there may not have been
one, but perhaps because the efficacy component drove the futility index
decision to terminate the trial early, and then you would not have the
opportunity, if you will, to have seen the safety issue.
So
that's where, I guess, I need to understand more fully what the futility index
definition was, how it was applied in this situation, and again what the safety
data then were at the time that the trials were terminated.
DR.
PACKER: I think probably the best way I
can answer that question is to again refer to the public presentation of the
data and the futility and the public presentation of the futility rule.
When
the results of the trial were first presented, they were first presented at a
European Society of Cardiology meetings in Oslo about -- I guess about a year
and a half ago. At that time, the
presentation indicated that the way the futility rule worked -- and I just
wrote this down -- was that the trial would be stopped because of futility.
If
the effect of the drug was sufficiently unfavorable to rule out an even ten
percent benefit, that would correspond.
That is the precise wording of what was presented during the
presentation. Does that help you? Does that answer your question?
DR.
MAKUCH: Okay. So is the answer then to my question that, if
it were -- if the trial was, in fact, going on the side of increased safety
concern on the part of the active drug,
then it would have been terminated prior to it actually crossing that
threshold?
DR.
PACKER: Yes.
DR.
MAKUCH: Thank you.
CHAIRMAN
ABRAMSON: I'll ask Dr. Siegel, because
we've discussed the CHF earlier in the day,
what the status of the labels is right now for each of these drugs.
DR.
UNGER: Well, when the results of these
trials became available, there were -- Basically, for the Enbrel label there
was a precaution in a CB -- changes being effected, and that precaution is in
the label that you have in front of you.
For
REMICADE, there was a contraindication and a warning placed in the label. Again, that is in front of you. For HUMIRA, there is nothing in the label.
One
of the questions that we have -- it is kind of implied in the question here --
is sort of similar to the question earlier when we were talking about lymphomas
for the committee. Would all TNF
blockers deserve the same language for heart failure? Does it appear to be a class effect or should
-- maybe there would be a simple statement in terms of, you know, class effect,
and then specific information where specific information exists.
Obviously,
we have a lot of specific information for etanercept and a fair amount of
information infliximab.
CHAIRMAN
ABRAMSON: Is it the precedent might be
the TB warning or the TB difference -- different language for infliximab and
etanercept with regard to TB precautions, one having a black box and the other
just a comment about -- a caution?
DR.
SIEGEL: I guess what Dr. Unger was
saying would be similar to the situation with TB in that all the labels contain
something about TB being observed in patients receiving TNF blocking agents,
including the agent that is in that particular label, and they would have more
specific language, for instance, the box warning, if the data indicated that.
CHAIRMAN
ABRAMSON: Dr. Williams.
DR.
WILLIAMS: To address the question, first
of all, I think that, since two of them have looked at it and found that it may
make heart failure worse, and the third one didn't look at it, it ought to
probably be in there as a caution on all of them.
I
would probably make it similar to all three and make it a caution rather than
the strong contraindication given to infliximab and state that it should be
used with care in patients who have congestive heart failure.
DR.
BOSCIA: We at least need a
contraindication at doses above 5 milligrams.
I mean, clearly, we had a problem with mortality at 10 milligrams, and
we at least need that for patient safety.
CHAIRMAN
ABRAMSON: Dr. Elashoff.
DR.
ELASHOFF: Okay. I don't have any particular comments on what
should be said in the label, but I do think that the data suggest that, for the
two compounds that it was studied, the data are suggestive in both cases that
one needs to be concerned and that the only reason we aren't concerned about
the other one is that they came along late enough not to make the same mistake
and study it.
So
I think we should have relatively consistent labeling on all three based on the
data we have at hand.
CHAIRMAN
ABRAMSON: So as a practical question,
one would be suggesting that the Enbrel label to be changed to be more
compatible with the REMICADE label?
DR.
WILLIAMS: I have to agree that if you've
got mortality, that we have to have the contraindication on infliximab, but I
think that the Enbrel label more accurately reflects things, and I would make
the adalimumab label more like the Enbrel than I would more like the
infliximab.
I
have a question for Jeff. I don't know
what he is asking when he says asked to develop additional procedures for CHF
risk management.
DR.
WEISS: In all fairness, I wrote the
question. So I can't blame it on Jeff,
but I'd like to. I guess -- I think it
stems from some of the analyses and data that Dr. Unger presented.
We
already know that people with preexisting heart disease, you know, should not
be taking this product. We know, though,
that heart disease is clearly a big health problem in the United States. It's clearly a big problem in people with
RA. In fact, I heart from my
rheumatology colleagues that cardiovascular disease is probably a higher --
it's elevated perhaps in the RA population.
I think everybody is nodding their head.
So I'm glad I'm not speaking in error here.
So
with that as a background -- So we have the area in the specific disease
setting in CHF where we know it's a bad thing and we shouldn't do that. Then we have here the indicated population,
large population, that are taking TNF blockers.
Some of them are clearly going to have underlying heart failure. Some of them are going to have a history,
predisposing factors, maybe not outright failure at the time that they are
started on therapy, but a history of it.
One
of Dr. Unger's analysis, albeit somewhat -- definitely an exploratory post
hoc analysis, tended to imply that even people with lesser degree -- at
least in one of the trials -- I guess it was the RENAISSANCE trial, the North
American trial, those with New York Heart Association II where you wouldn't
necessarily expect maybe these problems had perhaps more -- again, caveats
about being the subset analyses and retrospective -- that there was concerning
events in people with less severe forms of heart disease.
So
how does that help you in terms of trying to advise patients, what kinds of
information to put into label? Should
there be other methods that the companies could do, just like they did with
TB. There it's a little bit clearer. You can do screening and prophylaxis.
Are
there things that could be done with people with predisposition to heart
failure, with existing heart failure of some degree, who have bad RA and may
very well benefit from these products in terms of trying to improve the safety
profile?
Ellis,
if there is anything else you want to add --
DR.
UNGER: Another caveat is that, if I'm
not mistaken, heart failure is one of the most -- maybe the most common
diagnosis for a discharge summary, and there are many patients who are actually
misdiagnosed with, "heart failure."
So
again, that suggests that it might be worthwhile to have some kind of a
screening test to see if a patient actually has heart failure. Again, we are just kind of throwing out these
ideas.
DR.
WILLIAMS: I don't know that I can
address that specific what screening tests should be done, but there may be
people with mild heart failure who would benefit from these medications where
we can treat the heart failure and still allow them to take these
medications. That's why I didn't want to
see it as a strict contraindication.
I
can understand at higher doses, but as long as we can manage the heart failure,
they may still benefit from the medications.
But we have to be aware that we may make the heart failure worse by
giving them the medication.
CHAIRMAN
ABRAMSON: A question that harks back to
the capturing of information going forward and
standardized data being collected.
So the question is: Is heart
status part of the information that is being collected in these prospective
databases where lymphoma has been the primary outcome of interest?
DR.
WOLFE: Do you want me to answer that
question or do you want to go first?
CHAIRMAN
ABRAMSON: I guess one of the companies
could address that.
DR.
WOLFE: Okay. In the registry that we have, we collect all
information about cardiovascular diseases as well as all drugs that people are
taking for cardiovascular diseases, and we also ask them specifically if they
have had myocardial infarction, congestive heart failure, and we get all
medical hospitalization records.
So
we have a paper that has been submitted for publication. Based on 7,000 or so patients who were not
taking any TNF agent, the rate of heart failure -- prevalent rate of heart
failure was about 3.9 percent, that it was 2.8 percent on people who were
taking these drugs.
The
new cases which developed in people who had no previous history of any
cardiovascular disease suggested was about .18 percent in one group and
.20. These are all adjusted for severity
differences.
So
we found -- and we then did sensitivity analyses to look to see whether the
warning from the FDA might have reduced the participation of people with heart
failure by looking prior to the warning and also to making other
adjustments. As far as we can see, we do
not see any effect -- any increased rate of heart failure, and there is
actually a suggestion in the other direction.
Now
the other point is that these were -- Many people don't know they have heart
failure, of course, because when you get in the hospital and they do tests,
then they diagnose this. But the studies
that you are talking about are New York Heart Association III and IV, which are
very, very different than what is seen in the clinic generally.
So
I think the warning may be overstated.
DR.
UNGER: Actually, the RENAISSANCE and
RECOVER studies included patients who were -- about a quarter of the patients
were functional class II.
DR.
BLAYNEY: However, they did -- The
patients in those studies did have an ejection fraction of less than 30
percent. So these are not, you know,
mild heart failure people. These are
people with damaged hearts.
DR.
UNGER: Compensated heart failure, I
would say.
DR.
BLAYNEY: Yes, but they do have some
underlying --
DR.
UNGER: Dr. Packer disagrees, and he was
there.
DR.
PACKER: There is no relationship between
ejection fraction and severity of heart failure. Ejection fraction -- The only way we judge
severity of heart failure is really by symptoms, and the relationship between
ejection fraction and symptoms is pretty poor.
Almost
every trial we do enrolls people with ejection fractions less than 35 or 40
percent. Some of those trials are mild
heart failure. Some are moderate. Some are severe. So you can't make the judgment of mild based
on the ejection fraction, plus the fact, frankly speaking, although it is not
good medical practice, most people with heart failure in the United States are
managed without an ejection fraction -- without an ejection fraction
measurement. Yes, they have an ejection
fraction. We just don't measure it.
CHAIRMAN
ABRAMSON: Yes, sir?
DR.
GORE: Again my name is Jeff Gore. I'm also in New York like Milton, but at a
sister institution, the Wile Medical College.
I'm going to -- but we share a hospital.
It's the New York-Presbyterian Hospital.
I'm
going to try to respond to the questions you have raised and the question as
it's written. But before I do, let me
for Bob make a -- read the formal -- Milton stated it, but the formal written
-- Whoops, what happened to that slide, please?
Ah, there it is.
There
is the formal written statement of the early termination rule. The DSMB recognized that even by conservative
bounds that adjusted for the interim nature of the analysis, the confidence
interval for this estimate ruled out a ten percent benefit from etanercept,
crossing the established boundary for lack of efficacy on the morbidity
mortality endpoint.
It
was on that basis, that finding, that the trial was stopped and when
RENAISSANCE was stopped, RECOVER was stopped, because it was perceived that it
would be inappropriate to continue it if we were stopping for futility.
Now
having said that, let me move on. Milton
just made one of the key points here.
Screening for heart failure means you take a history and you do a
physical exam, which is being done, and you ask questions and all that kind of
stuff, and he can tell you, obviously, chapter and verse about that.
Let
me talk just a little bit about the data in response to the question here. In terms of worsening heart failure or death,
looking at the data we have just from the etanercept studies, because those are the only data that I really know
well, there was a modest tendency in RENAISSANCE for worsening. There was a modest tendency in the other
direction for improvement in RECOVER, very modest. I think nothing of either of them, albeit as
Bob pointed out earlier, the follow-up time in RECOVER was less than in
RENAISSANCE because of the early termination.
If
you put the two together in RENEWAL, there was a modest tendency toward
worsening. If you believe in statistical
adjustments -- and those are, of course, arbitrary algorithms. But if you believe in adjustment at all, at
least qualitatively, the existing modest tendency toward worsening becomes less
of a modest tendency toward worsening.
In
any event, in any of those analyses you do, even with observational statistics,
not adjusting for all the things that you would have to do if you were talking
about an efficacy endpoint, the consistency of those data don't reach the level
where you could draw a firm conclusion.
Nothing is close to statistical significance --
CHAIRMAN
ABRAMSON: Excuse me, Dr. Gore, if I may
just -- What I'd like to do is go back to the question, which is the label
change, for now.
DR.
GORE: Okay.
CHAIRMAN
ABRAMSON: I don't think we need to hear
more about the study, just because of -- in terms of addressing the question
here.
DR.
GORE: Oh, all right. I'm sorry.
I was responding to the question that was written here.
CHAIRMAN
ABRAMSON: Right. So do you want to just hold your comment just
for a second, because I don't want to get too diverted from the chart. You are addressing the screening, what
screening implementation should be, additional procedures for CHF, because
that's the second half of this question other than label?
DR.
GORE: Well, I was actually sort of
addressing the issue of whether there is something here to label about, but
okay.
CHAIRMAN
ABRAMSON: Why don't we just -- If you
just hold that thought, because I do want to come back to the question of
label.
Right
now we have two labels existent. For
etanercept we have a precaution, and for REMICADE we have more of a
warning. That's pretty much established. Are we being asked to address whether that
should be changed?
DR.
WEISS: Well, these -- Certainly for the
etanercept, it was submitted as what's called a CBE or changes being
effected. That means that the companies
can submit the changes, implement the changes.
The FDA has the opportunity to review them, but the idea is that safety
information is important and, while FDA is reviewing it for more data,
meanwhile the information isn't being communicated at all.
So,
therefore, in one of the last PADUFA negotiations there was a change. So that that information could actually be
directly added to the label without sort of an FDA concurrence, while then
allowing review to happen.
So
there's opportunities to -- I mean, things are never fixed, because there is
always new information coming up, whether it's safety or new efficacy in the
cases. So these labels are very
nonstatic, and we are constantly changing things.
Right
now, the way they are is what you see before you, but things have not been
finalized. There's still some
discussions going on and still some additional data under review. So it is a good opportunity, if not now, at
some relatively future day soon in the future to make any changes, if the
committee feels that there are important changes that should be made, whether
or not the wording is in the appropriate sections in the label or whether or
not there should be more similarities, etcetera. So --
CHAIRMAN
ABRAMSON: Okay. So, Dr. Gore, if you wouldn't mind, could you
focus on that issue, whether you think the proposed label should -- What
comment do you have on the label for Enbrel?
DR.
GORE: Yes. I think that the label, as it exists now with
the statement about, you know, there being some data that suggests maybe
something is going on, is perfectly adequate; because that's all you can say
from the information that is available.
The data just don't go any further than that.
If
you want me to support that statement with some information that you haven't
heard about today, I'd be happy to do that, but --
CHAIRMAN
ABRAMSON: I think we are okay, actually,
on the Enbrel, unless you are suggesting there be a change. Yes, Dr. Packer?
DR.
PACKER: I just want to express a
personal view based on my own view of the data.
I think it also reflects the view of many people in the heart failure
community, and it's a view that will be unpopular with everybody, and maybe
I'll be able to get home after stating it.
That
is that I wouldn't give any of these drugs to anyone with heart failure, and
people with heart failure are fragile.
When they get worse, sometimes you can't make them better. We are talking about some major issues here, issues I have
personal concerns about.
I
don't want to get into details as to whether the labeling should be the same or
different or whatever, but I think that there is a concern such that people
with heart failure in general shouldn't receive these drugs.
CHAIRMAN
ABRAMSON: So that gets at the specific
question, should all the labels, and I guess particularly -- What are the plans
for the HUMIRA label?
DR.
WEISS: Recognizing that that is clearly
not at all mentioned in the label and that there does appear to be this -- you
know, two out of the products have shown something, that there should be some
changes. I think that the company would
agree. So we will be discussing and have
already tentatively approached the company about making some changes to the
label. This discussion would help, I
think, facilitate that.
CHAIRMAN
ABRAMSON: Yes, Dr. Gore?
DR.
GORE: Yes. I'd just like to point out -- I mean,
obviously, Milton's opinion comes from years and years of working in this area
and is a very important opinion. But I
think it's not right to go beyond the data that we have, and I think it's very
important to remember, as I said earlier, we are talking about -- When we look
at the three agents that we are talking about here, we are talking about
substantially different molecules, and it's not really reasonable, I think, to
lump the results together and say the worst one is what tells us how they all
work.
I
think you have to say what you've got and give whatever cautionary information
you have, and then collect more data rather than saying, well, you know, what
we have now meets the test, and by golly, nobody should get this stuff.
So
you know, in terms of drug use as well as drug approvability, the issue of
efficacy and the issue of safety alone aren't the criteria for use or
approval. It's the relation between the
two, the benefit to risk relation.
What
we've seen from these data, at least from the etanercept data -- I don't know
about the others, but from the etanercept data we've seen a very modest
suggestion that something may get worse.
I could go on and defend that, but I won't.
We've
also seen a tremendous benefit. I think,
if you present that information to physicians, they can make a decision about
whether the relation of expected benefit to known or even suspected worse case
risk in patients with heart failure justifies the administration of the
drug. I think that's very important to
remember.
CHAIRMAN
ABRAMSON: So this is the difficult
question of class effect versus what data we have. Dr. Elashoff?
DR.
ELASHOFF: I just wanted to comment on
the issue of the statement that the data show only a modest risk, and it has to
do with the point that Dr. Makuch was making.
That is that the RENAISSANCE trial was stopped as soon as there was any
real evidence at all of risk and that it was prevented from ever going on and
possibly showing that the risk was higher.
The
stopping rule prevented us from ever demonstrating a bigger risk. Whether there might have been one or not, the
statistical stopping rule that was used prevented us from ever seeing a bigger
risk.
CHAIRMAN
ABRAMSON: Okay. Perhaps if there is a sense of the committee,
you have some discussions ongoing on infliximab and etanercept that are
graded. They are not the same, and you
have discussions with the Abbott company about some potential statement, as we
understand it.
I
think, unless someone else on the committee has a feeling that that shouldn't
be the way to go forward, we're probably not going to get much more out of this
part of the discussion.
DR.
WEISS: I just have something that is a
little bit unrelated, just for a second, just the comment that our
statisticians made, which I think is very important to highlight, and it's not
just with heart failure in these trials or with RENAISSANCE and RECOVER but in
other settings as well where trials are stopped early for futility and may or
may not have demonstrated harm and the whole concept that, you know, you don't
-- I think our view is that you don't have to prove harm to the same level that
you prove efficacy.
So
I mean, you know, just -- It's sometimes a misnomer. I mean, it's true that the trials are stopped
for futility if some of them happen to show some adverse trend. It's important to just look at those data and
not just brush it under as, well, it's just stopped for futility, and that was
it.
I
mean, clearly, there are trials that are stopped for outright harm, but in some
of these kinds of more gray areas where they are stopped early and you are not
going to know the answer, and you are never going to be able to do those
studies anymore to actually, you know, prove anything beyond -- you know, to
the level that you would want to prove efficacy.
CHAIRMAN
ABRAMSON: With respect to the last part
of that question number 1: Should the
companies be asked to develop additional procedures for CHF risk management?
I
could start off with a comment that we don't -- I think a label is an
appropriate thing to do. Asking
companies to do additional risk management may be premature or not -- in my own
view I'll express for the committee, and we can have comments -- but do we
need, like the other discussion, more information and as we collect more data
on treatment with these drugs, we need to get a better sense of the risk of CHF
in patients being treated with TNF blockers.
But my own view would be not to ask for new initiative on their parts,
given the information that we have.
DR. DAY:
There are a variety of risk management tools available. Did you have any in particular in mind that
you thought might be useful here? I
mean, it goes all the way from stickers on drugs to patient registries,
physician registries and so on. There's
a whole gamut here, and we are in a caution mode. But are there a couple you
would like us to think about?
DR.
WEISS: I'm really sorry I put that into
the question. I guess I was thinking
more along the lines of whether or not there's specific patient screening type
of things that could be done. You know,
we've already talked about patients should be closely monitored, you know,
carefully evaluated for worsening, and should be, you know, stopped in some cases. But whether or not there's any other ways to
try to evaluate patients that could be ask for.
But that was mostly what I was thinking.
CHAIRMAN
ABRAMSON: Okay. The last question is: Please comment on any other concerns based on
the safety updates provided and any specific actions the agency and the various
companies should undertake to address them.
I
think we may have covered the waterfront here.
DR.
WEISS: That was just in case -- I mean,
we did focus a lot on lymphoma. We
focused on CHF as a second area. We did
have a little bit of information and update on TB and addressed that. Some of the companies presented a little bit
more of the update.
A
lot of this was covered in August of '01
We just threw that out there as a sort of open-ended question in case
there's something else that the committee wanted to call to our attention, to
have us consider. We'd be happy to
entertain that, but if there isn't anything, that's also fine.
CHAIRMAN
ABRAMSON: I'm not sure if there isn't
anything or it's just five o'clock. Any
comments, additional comments? No. Okay.
So I guess we can adjourn. Thank
you all very much.
DR.
WEISS: Thank you, everybody on the
committee and guests.
(Whereupon,
the foregoing matter went off the record at 5:03 p.m.)