U.S. Food and Drug Administration
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BLA
BLA Supplement:
Supplement:
Etanercept
Etanercept Treatment
Treatment of
of
Pediatric
Pediatric Plaque
Plaque Psoriasis
Psoriasis
David
David L.
L. Kettl,
Kettl, MD
MD
Medical
Medical Officer
Officer
Division
Division of
of Dermatology
Dermatology and
and Dental
Dental Products
Products
Office
Office of
of Drug
Drug Evaluation
Evaluation III
III
Food
Food and
and Drug
Drug Administration
Administration
FDA
FDA DODAC
DODAC Meeting
Meeting
June
June 18,
18, 2008
2008
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
1
Presentation
Presentation Overview
Overview
• Background
• Efficacy
• Safety
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
2
Proposed
Proposed Indication
Indication
Treatment of chronic moderate to severe
plaque psoriasis in pediatric patients
who are inadequately controlled with
topical psoriasis therapy or who have
received systemic therapy or
phototherapy.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
3
Pediatric
-Epidemiology
Pediatric Psoriasis
Psoriasis-Epidemiology
•• Psoriasis
Psoriasis prevalence
prevalence estimated
estimated to
to be
be 0.32%
0.32% in
in
children
children << 18
18 years
years of
of age
age (NCHS-CDC,
(NCHS-CDC, 1996)
1996)
•• Most
Most children
children do
do not
not have
have severe
severe disease
disease and
and topical
topical
treatment
treatment is
is usually
usually sufficient
sufficient (Benoit,
(Benoit, 2007,
2007, Paller
Paller
and
and Mancini,
Mancini, 2006)
2006)
•• Age
Age of
of onset
onset in
in not
not predictive
predictive of
of disease
disease severity
severity
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
4
Plaque
Plaque Psoriasis
Psoriasis Treatment:
Treatment:
Topical
Topical Therapies
Therapies
Most
Most pediatric
pediatric plaque
plaque psoriasis
psoriasis is
is
controlled
controlled with
with topical
topical therapy
therapy alone.
alone.
•• Emollients
Emollients
•• Topical
Topical corticosteroids–
corticosteroids– (High
(High potency
potency steroids
steroids e.g.,
e.g.,
betamethasone
betamethasone dipropionate,
dipropionate, clobetasol
clobetasol and
and
halobetamethasone
halobetamethasone -- approved
approved in
in 12
12 years
years and
and older)
older)
•• Tars—anti-inflammatory
Tars—anti-inflammatory and
and anti-proliferative
anti-proliferative
•• Anthralin
Anthralin
•• Calcipotriene—Vitamin
Calcipotriene—Vitamin D
D33 analogue
analogue
•• Topical
Topical Retinoids—tazarotene
Retinoids—tazarotene (12
(12 and
and over)
over)
•• Calcineurin
Calcineurin inhibitors—tacrolimus
inhibitors—tacrolimus
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
5
Psoriasis
Psoriasis Treatment:
Treatment:
Systemic
Systemic Therapy
Therapy
•• Methotrexate—folic
Methotrexate—folic acid
acid antagonist
antagonist
•• Cyclosporine
Cyclosporine
•• Oral
Oral Retinoids—Acitretin
Retinoids—Acitretin
•• Phototherapy
Phototherapy –– with
with or
or without
without psoralen
psoralen
•• Biologic
Biologic products
products
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
6
Systemic
Systemic Biologic
Biologic Products
Products Approved
Approved for
for
Adult
Adult Plaque
Plaque Psoriasis
Psoriasis
•• Anti-TNFα
Anti-TNFα products
products
––
––
––
Etanercept
Etanercept (Enbrel)
(Enbrel) -- fusion
fusion protein
protein (4/04)
(4/04)
Infliximab
Infliximab (Remicade)
(Remicade) -- monoclonal
monoclonal antibody
antibody (9/06)
(9/06)
Adalimumab
Adalimumab (Humira)
(Humira) -- monoclonal
monoclonal antibody
antibody (1/08)
(1/08)
•• Anti-T
Anti-T cell
cell surface
surface protein
protein products
products
––
––
Alefacept
Alefacept (Amevive)
(Amevive) -- fusion
fusion protein
protein (1/03)
(1/03)
Efalizumab
Efalizumab (Raptiva)
(Raptiva) -- monoclonal
monoclonal antibody
antibody (10/03)
(10/03)
No
No Biologic
Biologic Product
Product is
is Approved
Approved
for
for Pediatric
Pediatric Plaque
Plaque Psoriasis
Psoriasis
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
7
Pediatric
Pediatric Indications
Indications for
for Biologics
Biologics
Drug
Drug
Indication
Indication
Ages
Ages
Trial
Trial Subjects
Subjects
Adalimumab
Adalimumab
JIA
JIA
4-17
4-17
171
171
Infliximab
Infliximab
JIA
JIA (failed
(failed efficacy)
efficacy)
Crohn’s
Crohn’s
4-17
4-17
6-17
6-17
60
60
112
112
Etanercept
Etanercept
JIA
JIA
4-17
4-17
69
69
Alefacept,
Alefacept, efalizumab,
efalizumab, certolizumab
certolizumab have
have no
no pediatric
pediatric indications.
indications.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
8
Etanercept
Etanercept Approved
Approved Indications
Indications
Indications
Indications (date
(date of
of initial
initial Agency
Agency approval):
approval):
•• Rheumatoid
Rheumatoid Arthritis
Arthritis
(November
(November 2,
2, 1998)
1998)
•• Juvenile
Juvenile Idiopathic
Idiopathic Arthritis
Arthritis
(May
(May 27,
27, 1999)
1999)
–– Only
Only approved
approved pediatric
pediatric indication-age
indication-age 22
•• Psoriatic
Psoriatic Arthritis
Arthritis
(January
(January 15,
15, 2002)
2002)
•• Ankylosing
Ankylosing Spondylitis
Spondylitis
(July
(July 24,
24, 2003)
2003)
•• Plaque
Plaque Psoriasis
Psoriasis (age
(age 18)
18)
(April
(April 30,
30, 2004)
2004)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
9
April
April 2004
2004
Post
-Marketing Commitments
Post-Marketing
Commitments
•• Pediatric
Pediatric study
study 20030211—Current
20030211—Current application
application
•• Adult
Adult 22 year
year efficacy
efficacy and
and safety
safety
–– 20030117
20030117 Study
Study report
report submitted
submitted and
and is
is under
under review
review
•• Long
Long term
term surveillance
surveillance of
of serious
serious adverse
adverse events
events
(infections
(infections and
and malignancies)-2500
malignancies)-2500 subjects
subjects for
for five
five
years
years
–– 20040210
20040210 Protocol
Protocol details
details in
in discussion;
discussion; Study
Study report
report expected
expected
2013
2013
•• Exposed
Exposed pregnancy
pregnancy registry
registry for
for all
all indications
indications
–– 20040246
20040246 Study
Study report
report expected
expected 2012
2012
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
10
Study
Study 20030211
20030211
Period
Period A:
A:
Initial
Initial 12
12 week
week randomized,
randomized, doubledoubleblind,
blind, placebo-controlled
placebo-controlled
Period
Period B:
B:
24
24 week
week open
open label
label treatment
treatment
Period
Period C:
C:
12
12 week
week randomized,
randomized, double-blind,
double-blind,
placebo
placebo vs.
vs. continued
continued treatment
treatment
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
11
Study
Study 2003211
2003211
•• 211
211 subjects
subjects age
age 4-17
4-17 years
years with
with moderate
moderate to
to severe
severe
plaque
plaque psoriasis
psoriasis in
in 42
42 US
US and
and Canadian
Canadian study
study sites
sites
•• Primary
Primary endpoint
endpoint was
was 75%
75% or
or greater
greater improvement
improvement
from
from baseline
baseline in
in the
the psoriasis
psoriasis area-and-severity
area-and-severity index
index
(PASI
(PASI 75)
75) at
at week
week 12
12
•• Secondary
Secondary endpoints
endpoints included
included aa physician's
physician's global
global
assessment
assessment (sPGA)
(sPGA) of
of 00 or
or 11 on
on aa 00 to
to 55 point
point scale
scale
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
12
Baseline
Baseline Characteristics
Characteristics
•• PGA
PGA ≥≥ 3;
3; BSA
BSA ≥≥ 10%;
10%; PASI
PASI ≥≥ 12
12
•• Median
Median PASI
PASI was
was 16
16 (12-56)
(12-56)
•• 120
120 (57%)
(57%) had
had previous
previous systemic
systemic or
or photo
photo therapy
therapy
•• Guttate,
Guttate, erythrodermic,
erythrodermic, and
and pustular
pustular psoriasis
psoriasis were
were
excluded
excluded
•• 19
19 (9%)
(9%) subjects
subjects self
self reported
reported psoriatic
psoriatic arthritis
arthritis –– no
no
baseline
baseline physical
physical evaluation
evaluation was
was performed
performed to
to
characterize
characterize severity
severity
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
13
Efficacy
Efficacy Issues
Issues
••
••
••
••
••
••
••
Higher
Higher placebo
placebo response
response than
than adult
adult studies
studies
Few
Few subjects
subjects cleared
cleared their
their disease
disease
Efficacy
Efficacy wanes
wanes over
over last
last period
period of
of trial
trial
Few
Few subjects
subjects had
had severe
severe disease
disease
Variability
Variability between
between sPGA
sPGA and
and PASI
PASI
assessments
assessments
Some
Some subjects
subjects appear
appear to
to have
have less
less disease
disease
from
from photographs
photographs when
when compared
compared to
to PGA
PGA
score
score
Subjects
Subjects were
were heavier
heavier and
and larger
larger than
than age
age
matched
matched peers
peers
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
14
Period
Period A
A -- Week
Week 12
12 Efficacy
Efficacy
Etanercept
N = 106
Placebo
N = 105
sPGA
Number of successes (%)
+
p-value
55 (51.9%) 14 (13.3%)
<0.0001
PASI 75
Number of Successes (%)
p-value+
60 (56.6%) 12 (11.4%)
<0.0001
+
P-value was calculated using CMH test, stratified by age group.
All missing values were imputed as failures.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
15
Period
Period A
A -- Week
Week 12
12 Efficacy
Efficacy
Etanercept
N = 106
Placebo
N = 105
PASI 50
79 (74.5%)
24 (22.9%)
PASI 90
29 (27.4%)
7 (6.7%)
PASI 100
7 (6.6%)
2 (1.9%)
All missing values were imputed as failures.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
16
Proportion
Proportion of
of successes
successes in
in Periods
Periods
A
A and
and B
B --- sPGA
sPGA and
and PASI
PASI
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
17
Period
Period C
C Efficacy:
Efficacy:
Endpoint
Week
Etanercept
N = 68
Placebo
N = 69
sPGA
36
40
44
48
51 ( 75.0%)
41 ( 62.1%)
38 ( 55.1%)
33 ( 47.8%)
52 ( 75.4%)
42 (60.9%)
30 (43.5%)
27 ( 39.1%)
PASI 75
36
40
44
48
64 ( 94.1%)
54 ( 79.4%)
49 (72.1%)
44 (64.7%)
65 (94.2%)
52 (75.4%)
40 (58.0%)
34 (49.3%)
All missing values were imputed as failures.
Source: Reviewer analysis
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
18
Period
Period C
C -- Maintenance
Maintenance of
of efficacy
efficacy
over
over time,
time, sPGA
sPGA and
and PASI:
PASI:
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
19
Subjects
Subjects who
who were
were treated
treated with
with
etanercept
etanercept for
for 48
48 weeks
weeks (n=31)
(n=31)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
20
Subject
Subject Baseline
Baseline Disease
Disease Severity:
Severity:
Static Physician Global Assessment of Psoriasis at Baseline
PGA Score
Placebo (105) Etanercept (106) All (211)
0
1
2
3
4
5
0
0
1
68
33
3
(0%)
(0%)
(1%)
(65%)
(31%)
(3%)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
0
0
1
69
33
3
(0%)
(0%)
(1%)
(65%)
(31%)
(3%)
0
0
2
137
66
6
(0%)
(0%)
(1%)
(65%)
(31%)
(3%)
21
Comparison
Comparison of
of Baseline
Baseline PGA
PGA and
and PASI
PASI Scores
Scores
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Range:
PGA
Range:
PGA 33 –– 12.0
12.0 –– 34.0
34.0
PGA
PGA 44 ---- 12.0
12.0 -- 56.7
56.7
22
PGA
PGA 55 –– 13.2
13.2 –– 51.6
51.6
Subject
Subject with
with Baseline
Baseline
Investigator
Investigator Scored
Scored PGA
PGA of
of 55
Baseline: PASI 51.6
PGA: 5
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Week 12: PASI 12.1
PGA 1
23
Photos
Photos of
of Subject
Subject 11 with
with Baseline
Baseline
Investigator
Investigator Scored
Scored with
with PGA
PGA of
of 44
Baseline: PASI 22.8
PGA:
PGA: 55
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Week 12: PASI 2.7
PGA:2
PGA:2
24
Photos
Photos of
of Subject
Subject 11 with
with Baseline
Baseline
Investigator
Investigator Scored
Scored with
with PGA
PGA of
of 44
Baseline: PASI 22.8
PGA:
PGA: 44
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Week 12: PASI 2.7
PGA:
PGA: 22
25
Photos
Photos of
of Subject
Subject 22 with
with Baseline
Baseline
Investigator
Investigator Scored
Scored with
with PGA
PGA of
of 44
Baseline: PASI 12.6
PGA:
PGA: 44
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Week 12: PASI 0.3
PGA:
PGA: 11
26
Photos
Photos of
of Subject
Subject 22 with
with Baseline
Baseline
Investigator
Investigator Scored
Scored with
with PGA
PGA of
of 44
Baseline: PASI 12.6
PGA:
PGA: 44
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
Week 12: PASI 0.3
PGA:
PGA: 11
27
Baseline
Baseline Subject
Subject Treatment
Treatment Arm
Arm
Distribution
Distribution by
by Age
Age
Age Group
Placebo
n
Etanercept
n
All
n
4-11 years
38
38
76
12-17 years
67
68
135
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
28
Baseline
Baseline Subject
Subject Weight
Weight
Distribution
Distribution by
by Age
Age
Age Group
Mean
Weight
Weight
Range
Mean BMI
4-11 years
81 lbs
(37 kg)
37 to 169
lbs
19.8
12-17 years
165 lbs
(75 kg)
83 to 363
lbs
27.0
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
29
Safety
Safety
• Clinical trial adverse events
–– 22 subjects
subjects with
with serious
serious infections
infections
• Warnings and Precautions in current
labeling
–– Boxed
Boxed warning
warning added
added March,
March, 2008
2008
• Post-marketing adverse event reporting
–– FDA
FDA Early
Early Communication
Communication regarding
regarding malignancies
malignancies in
in
pediatric
pediatric patients
patients who
who use
use TNF
TNF blockers-June,
blockers-June, 2008
2008
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
30
Study
Study Safety
Safety Assessment
Assessment
••
Serious
Serious Adverse
Adverse Infection
Infection Events
Events on
on Etanercept
Etanercept
–– 77 year
year old
old with
with LLL
LLL pneumonia
pneumonia hospitalized
hospitalized for
for
IV
IV antibiotics
antibiotics
––
••
99 year
year old
old with
with gastroenteritis
gastroenteritis required
required
hospitalization
hospitalization and
and IV
IV rehydration
rehydration
Herpes
Herpes zoster
zoster (shingles)in
(shingles)in two
two subjects
subjects with
with prior
prior
documented
documented immunity
immunity at
at baseline
baseline
–– 12
12 year
year old
old girl
girl and
and 11
11 year
year old
old boy
boy (both
(both had
had
chickenpox
chickenpox disease
disease at
at age
age 3)
3)
(AAP
(AAP Red
Red Book:
Book: Background
Background rate
rate of
of 0.68
0.68 per
per
1000
1000 in
in patients
patients << 20
20 years)
years)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
31
Adverse
Adverse Events
Events >>3%
3%of
ofsubjects
subjects from
from Period
Period AA
Adverse Events that Occurred in at Least 3% of Subjects ( Period A)
Preferred Term
Etanercept
N = 106
Placebo
N = 105
Headache
18 ( 17.0%)
18 ( 17.1%)
Upper respiratory tract infection
18 (17.0%)
13 ( 12.4%)
Nasopharyngitis
10 ( 9.5%)
10 ( 9.5%)
Influenza
8 ( 7.5%)
3 ( 2.9%)
Arthralgia
7 ( 6.6%)
0
Dizziness
6 ( 5.7%)
1 ( 1.0%)
Gastroenteritis
6 ( 5.7%)
0
Injection site pain
6 ( 5.7%)
0
Vomiting
5 ( 4.7)
2 ( 1.9%)
Cough
4 ( 3.8%)
2 ( 1.9%)
Pharyngolaryngeal pain
1 ( <1%)
6 ( 5.7%)
Pharyngitis
2 ( 1.9%)
5 ( 4.8%)
Diarrhea
1 ( <1%)
4 ( 3.8%)
Injection site bruising
1 ( <1%)
4 ( 3.8%)
Source: Reviewer analysis
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
32
Antibiotic
Antibiotic Use
Use during
during Clinical
Clinical Trial
Trial
More
More subjects
subjects on
on etanercept
etanercept used
used an
an antibiotic
antibiotic as
as
compared
compared to
to placebo
placebo during
during Period
Period A
A and
and thereafter.
thereafter.
Subjects who had at
least one antibiotic
medication
Originally on
Etanercept during
Period A
Originally on
Placebo during
Period A
Period A
27 (25.5%)
21 (20.0%)
52 (49.1%)
45 (42.9%)
After Period A
(Periods B, C, and
Incomplete
Responders)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
33
Etanercept
Etanercept Boxed
Boxed Warning
Warning
March
March 2008
2008
“Infections,
“Infections, including
including serious
serious infections
infections leading
leading to
to hospitalization
hospitalization
or
or death,
death, have
have been
been observed
observed in
in patients
patients treated
treated with
with ENBREL
ENBREL
(see
(see WARNINGS
WARNINGS and
and ADVERSE
ADVERSE REACTIONS).
REACTIONS). Infections
Infections have
have
included
included bacterial
bacterial sepsis
sepsis and
and tuberculosis.
tuberculosis. Patients
Patients should
should be
be
educated
educated about
about the
the symptoms
symptoms of
of infection
infection and
and closely
closely monitored
monitored
for
for signs
signs and
and symptoms
symptoms of
of infection
infection during
during and
and after
after treatment
treatment
with
with ENBREL.
ENBREL. Patients
Patients who
who develop
develop an
an infection
infection should
should be
be
evaluated
evaluated for
for appropriate
appropriate antimicrobial
antimicrobial treatment
treatment and,
and, in
in
patients
patients who
who develop
develop aa serious
serious infection,
infection, ENBREL
ENBREL should
should be
be
discontinued…”
discontinued…”
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
34
Cancer
Cancer Risk:
Risk: Ongoing
Ongoing Assessment
Assessment
An
An Early
Early Communication
Communication about
about an
an Ongoing
Ongoing Safety
Safety
Review
Review was
was issued
issued on
on June
June 4,
4, 2008.
2008.
•• Adverse
Adverse event
event reports
reports of
of lymphoma
lymphoma and
and other
other
malignancies
malignancies with
with Enbrel
Enbrel and
and other
other TNF
TNF blockers
blockers in
in
the
the treatment
treatment of
of JIA
JIA (JRA)
(JRA) and
and other
other pediatric
pediatric
conditions
conditions
•• Approximately
Approximately 30
30 cases
cases of
of cancer
cancer in
in children
children and
and
young
young adults
adults who
who were
were treated
treated with
with TNF
TNF blockers
blockers
over
over aa 10
10 year
year period.
period.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
35
Agency
Agency Discussion
Discussion on
on Cancer
Cancer Risk
Risk
Jeffrey
Jeffrey Siegel,
Siegel, M.D.,
M.D., DARRP
DARRP
Hyon
Hyon Kwon,
Kwon, Pharm.D.,
Pharm.D., M.P.H.,
M.P.H., DAEA
DAEA I,I, OSE
OSE
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
36
Conclusions
Conclusions for
for Etanercept
Etanercept for
for
Pediatric
Pediatric Plaque
Plaque Psoriasis
Psoriasis
1)
1) There
There may
may still
still be
be informational
informational needs
needs regarding
regarding the
the
safety
safety and
and efficacy
efficacy of
of etanercept
etanercept to
to inform
inform
prescribers,
prescribers, patients
patients and
and their
their parents
parents for
for this
this nonnonlife
life threatening
threatening pediatric
pediatric indication.
indication.
2)
2) The
The Committee
Committee is
is asked
asked to
to comment
comment on
on the
the
adequacy
adequacy of
of the
the safety
safety and
and efficacy
efficacy assessments
assessments
for
for the
the pediatric
pediatric age
age group,
group, and
and how
how those
those
informational
informational needs
needs should
should be
be addressed.
addressed.
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
37
Back
Back Up
Up Slides
Slides
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
38
Study
Study Algorithm
Algorithm
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
39
Etanercept
Etanercept (Enbrel)
(Enbrel) for
for Pediatric
Pediatric
Plaque
—Study 211
Plaque Psoriasis
Psoriasis—Study
211
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
40
Pediatric
—Epidemiology
Pediatric Psoriasis
Psoriasis—Epidemiology
Age
Ageof
ofonset
onsetof
ofpsoriasis
psoriasis(Raychaudhuri
(Raychaudhuriet
etal.,
al.,2000)
2000)
FDA Dermatologic and Ophthalmic Drugs Advisory
Committee, June 18, 2008
41
Safety
-Blocking Agents
Safety of
of TNF
TNF-Blocking
Agents
Jeffrey
Jeffrey N.
N. Siegel,
Siegel, M.D.
M.D.
FDA/CDER/ODE2/DAARP
FDA/CDER/ODE2/DAARP
Dermatologic
Dermatologic and
and Ophthalmic
Ophthalmic Drugs
Drugs Advisory
Advisory
Committee
Committee
June
June 18,
18, 2008
2008
Center for Drug Evaluation and Research
TNF
TNF Blocking
Blocking Agents
Agents Approved
Approved in
in
Adults
Adults
• Infliximab (Remicade) and etanercept
(Enbrel) first TNF blockers approved:
1998
• Adalimumab (Humira) approved in
1999
• Certolizumab (Cimzia) approved for
Crohn’s disease in 2008
DODAC Meeting
June 18, 2008
2
TNF
TNF Blockers:
Blockers: Benefits
Benefits &
& Risks
Risks
•• Infliximab,
Infliximab, etanercept
etanercept and
and adalimumab
adalimumab are
are
approved
approved for
for inflammatory
inflammatory arthritides
arthritides (RA,
(RA, PsA,
PsA,
AS)
AS) and
and psoriasis
psoriasis
•• Infliximab,
Infliximab, adalimumab
adalimumab and
and certolizumab
certolizumab also
also
approved
approved for
for Crohn’s
Crohn’s disease
disease
•• Studies
Studies of
of three
three products
products approved
approved for
for
inflammatory
inflammatory arthritides
arthritides have
have demonstrated
demonstrated high
high
response
response rates
rates in
in patients
patients not
not responsive
responsive to
to
conventional
conventional disease-modifying
disease-modifying drugs
drugs (DMARD’s)
(DMARD’s)
•• Each
Each associated
associated with
with uncommon,
uncommon, but
but serious
serious
adverse
adverse events
events
•• In
In indicated
indicated patient
patient population,
population, benefits
benefits outweigh
outweigh
potential
potential risks
risks
DODAC Meeting
June 18, 2008
3
TNF
TNF Blockers
Blockers Approved
Approved in
in
Children
Children
•• Etanercept
Etanercept approved
approved in
in 1999
1999 for
for use
use in
in
children
children with
with juvenile
juvenile idiopathic
idiopathic arthritis
arthritis
(JIA)
(JIA) based
based on
on study
study showing
showing efficacy
efficacy in
in
patients
patients refractory
refractory to
to conventional
conventional
therapies
therapies
–– Currently
Currently approved
approved age
age 22 and
and older
older
•• Adalimumab
Adalimumab recently
recently approved
approved for
for JIA
JIA age
age
44 and
and older
older
•• Infliximab
Infliximab approved
approved for
for children
children with
with
Crohn’s
Crohn’s disease
disease age
age 66 and
and older
older
•• In
In general,
general, safety
safety in
in children
children similar
similar to
to
adults
adults
DODAC Meeting
June 18, 2008
4
Clinical
Clinical Trials
Trials for
for Pediatric
Pediatric
Approvals
Approvals
•• Extensive
Extensive safety
safety information
information available
available in
in adults
adults at
at
time
time of
of pediatric
pediatric approvals
approvals
•• Etanercept
Etanercept for
for JIA:
JIA:
–– 69
69 children
children age
age 4-17:
4-17: initial
initial 3-month
3-month open-label
open-label
lead-in
lead-in then
then randomized
randomized withdrawal
withdrawal (up
(up to
to 44
months)
months) followed
followed by
by open-label
open-label extension
extension
•• Infliximab
Infliximab in
in pediatric
pediatric Crohn’s
Crohn’s disease
disease
–– 112
112 children
children age
age 6-17:
6-17: 1-year
1-year randomized,
randomized, openopenlabel
label comparison
comparison of
of two
two treatment
treatment regimens
regimens
added
added to
to background
background immunosuppressive
immunosuppressive
•• Adalimumab
Adalimumab for
for JIA
JIA
–– 117
117 children
children age
age 4-17:
4-17: initial
initial open-label
open-label lead-in
lead-in
then
then randomized
randomized withdrawal
withdrawal followed
followed by
by openopenlabel
label extension
extension
–– 2-year
2-year data
data available
available at
at time
time of
of approval
approval
DODAC Meeting
June 18, 2008
5
Serious
Serious Adverse
Adverse Events
Events Associated
Associated
With
With TNF
TNF Blocking
Blocking Agents
Agents
•• Serious
Serious infections
infections
–Tuberculosis
–Tuberculosis
–Opportunistic
–Opportunistic infections
infections (e.g.
(e.g.
histoplasmosis,
histoplasmosis, listeriosis,
listeriosis,
coccidiodomycosis,
coccidiodomycosis, PCP)
PCP)
–Non-opportunistic
–Non-opportunistic infections
infections
•• Demyelinating
Demyelinating events
events
•• Autoantibodies
Autoantibodies &
& Autoimmune
Autoimmune disease
disease
•• Malignancies
Malignancies
DODAC Meeting
June 18, 2008
Mechanisms
Mechanisms Underlying
Underlying Serious
Serious
Adverse
Adverse Events
Events (SAEs)
(SAEs)
• Some SAEs expected based on
mechanism of action, i.e.,
immunosuppression: TB, serious
infections
• Other SAE’s unexpected:
demyelinating disease, exacerbation
of severe CHF
DODAC Meeting
June 18, 2008
7
Risk
Risk of
of Malignancy
Malignancy
• Potential risk of malignancy has
been a concern since initial
approvals
• Because of immunosuppressive
properties, possibility for reduced
immune surveillance and malignancy
risk
• However, data are conflicting
DODAC Meeting
June 18, 2008
8
Lymphoma
Lymphoma Risk
Risk in
in Adults
Adults
•• Risk
Risk of
of lymphoma
lymphoma first
first noted
noted when
when imbalance
imbalance
seen
seen for
for lymphomas
lymphomas in
in pooled
pooled controlled
controlled clinical
clinical
trials
trials of
of three
three TNF
TNF blockers
blockers
–– However,
However, other
other potential
potential explanations,
explanations, e.g.,
e.g.,
unequal
unequal (3:1)
(3:1) allocation
allocation to
to drug
drug &
& placebo
placebo
arms
arms
•• In
In overall
overall clinical
clinical trial
trial experience,
experience, relative
relative risk
risk
approximately
approximately 33- to
to 5-fold
5-fold with
with TNF
TNF blockers
blockers
compared
compared to
to general
general population
population
•• However,
However, similar
similar relative
relative risk
risk noted
noted in
in RA
RA
patients
patients with
with highly
highly active
active disease
disease not
not receiving
receiving
TNF
TNF blockers
blockers
•• Epidemiologic
Epidemiologic studies
studies have
have suggested
suggested similar
similar
rates
rates of
of lymphoma
lymphoma in
in adult
adult patients
patients with
with RA
RA
treated
treated with
with TNF
TNF blockers
blockers compared
compared to
to patients
patients
not
not receiving
receiving TNF
TNF blockers
blockers
DODAC Meeting
June 18, 2008
9
Hepatosplenic
Hepatosplenic TT Cell
Cell Lymphoma
Lymphoma
(HSTL)
(HSTL)
• Rare cases of HSTL have been
observed in adolescents and young
adults with Crohn’s disease
receiving infliximab
• HSTL is a rare, aggressive T cell
lymphoma that is usually fatal
• All cases associated with
concomitant immunosuppressives
azathioprine or 6-mercaptopurine
DODAC Meeting
June 18, 2008
10
Risk
Risk of
of Solid
Solid Malignancies
Malignancies in
in
Adults
Adults
•• When
When AEs
AEs of
of malignancy
malignancy assessed
assessed in
in randomized
randomized
trials
trials higher
higher rate
rate seen
seen for
for infliximab,
infliximab, adalimumab
adalimumab
than
than controls
controls
–– Infliximab
Infliximab 0.52/100
0.52/100 patient-years
patient-years vs.
vs. 0.11/100
0.11/100
pt-yrs
pt-yrs in
in controls
controls
–– Adalimumab
Adalimumab 0.6/100
0.6/100 pt-yrs
pt-yrs vs.
vs. 0.4/100
0.4/100 pt-yrs
pt-yrs
with
with controls
controls
–– Variety
Variety of
of solid
solid tumors
tumors typical
typical in
in general
general
population
population
–– For
For infliximab,
infliximab, adalimumab
adalimumab malignancy
malignancy rate
rate
not
not higher
higher than
than expected
expected rate
rate in
in general
general
population
population
•• Relatively
Relatively short
short time
time of
of observation,
observation, unequal
unequal
randomization
randomization make
make interpretation
interpretation uncertain
uncertain
•• With
With etanercept
etanercept rate
rate not
not higher
higher than
than controls
controls
DODAC Meeting
June 18, 2008
11
Risk
Risk of
of Solid
Solid Malignancies
Malignancies (cont.)
(cont.)
• Amgen recently submitted to FDA a
draft report on an independent metaanalysis of clinical trials to assess
cancer risk for approved TNF
blockers, including etanercept
• The draft report is under FDA review
• Final report expected shortly
DODAC Meeting
June 18, 2008
12
Solid
Solid Malignancies
Malignancies in
in Adults
Adults
•• Randomized
Randomized trial
trial data
data inconclusive
inconclusive for
for
risk
risk of
of solid
solid tumors
tumors
•• In
In long-term
long-term treatment
treatment studies
studies no
no
evidence
evidence for
for increasing
increasing rate
rate with
with longer
longer
exposure
exposure
•• Epidemiologic
Epidemiologic studies
studies conducted
conducted in
in
England,
England, Sweden
Sweden have
have shown
shown no
no
increased
increased rate
rate of
of malignancies
malignancies in
in adults
adults
with
with RA
RA receiving
receiving TNF
TNF blockers
blockers
DODAC Meeting
June 18, 2008
13
Malignancies
Malignancies in
in Unapproved
Unapproved
Indications
Indications
•• Two
Two controlled
controlled trials
trials have
have suggested
suggested malignancy
malignancy
signal
signal in
in certain
certain patient
patient populations
populations
•• In
In aa randomized,
randomized, controlled
controlled trial
trial of
of etanercept
etanercept in
in
Wegener’s
Wegener’s granulomatosis,
granulomatosis, 5/89
5/89 patients
patients in
in the
the
etanercept
etanercept arm
arm developed
developed solid
solid malignancies
malignancies vs.
vs.
none
none in
in controls
controls
–– All
All occurred
occurred in
in the
the subgroup
subgroup receiving
receiving
concomitant
concomitant cyclophosphamide
cyclophosphamide
•• In
In aa randomized,
randomized, controlled
controlled trial
trial in
in moderate
moderate to
to
severe
severe COPD,
COPD, 9/57
9/57 infliximab-treated
infliximab-treated patients
patients
developed
developed malignancies
malignancies vs.
vs. 1/77
1/77 controls
controls
(7.67/100
(7.67/100 pt-yrs
pt-yrs vs.
vs. 1.63/100
1.63/100 pt-yrs)
pt-yrs)
•• Data
Data suggest
suggest that
that in
in certain
certain populations
populations at
at high
high
risk
risk of
of malignancy
malignancy risk
risk may
may be
be increased
increased by
by
treatment
treatment with
with TNF
TNF blockers
blockers
DODAC Meeting
June 18, 2008
14
Malignancies
Malignancies in
in Children
Children
Receiving
Receiving TNF
TNF Blockers
Blockers
• Recently, FDA has become aware of
post-marketing reports of
malignancies in children receiving
TNF blockers
• Overall approximately 30 cases have
been reported (excluding HSTL)
• Reports of malignancies in children
have occurred in both JIA and
Crohn’s disease
DODAC Meeting
June 18, 2008
15
Malignancies
Malignancies in
in Children
Children
Receiving
Receiving TNF
TNF Blockers
Blockers (cont.)
(cont.)
•• Approximately
Approximately half
half are
are lymphomas
lymphomas and
and
half
half are
are other
other malignancies
malignancies
•• Lymphomas
Lymphomas include
include Hodgkin’s
Hodgkin’s disease
disease
and
and non-Hodgkin’s
non-Hodgkin’s lymphoma
lymphoma
•• Other
Other malignancies
malignancies include
include leukemia,
leukemia,
melanoma,
melanoma, other
other solid
solid organ
organ cancers
cancers
•• Rate
Rate of
of malignancy
malignancy compared
compared to
to
background
background rate,
rate, relationship
relationship to
to use
use of
of
TNF
TNF blockers
blockers currently
currently under
under
investigation
investigation
DODAC Meeting
June 18, 2008
16
Safety
Safety Data
Data from
from Registries
Registries
•• To
To assess
assess long-term
long-term safety
safety of
of biologics
biologics in
in
children,
children, observational
observational registries
registries were
were
established
established at
at time
time of
of approvals
approvals for
for
pediatric
pediatric use:
use:
–– Established
Established to
to fulfill
fulfill post-marketing
post-marketing
commitments/requirements
commitments/requirements
•• Etanercept
Etanercept registry
registry for
for JIA,
JIA, infliximab
infliximab
registry
registry for
for pediatric
pediatric Crohn’s
Crohn’s
•• Adalimumab
Adalimumab registry
registry for
for JIA
JIA recently
recently
begun.
begun.
DODAC Meeting
June 18, 2008
17
Observational
Observational Registry:
Registry:
Etanercept
Etanercept
• Study designed to collect data on
long-term use of etanercept in JIA
alone or in combination with MTX
• Enrollment completed 1/05:
– 103 on etanercept alone (224 pt-yrs)
– 294 on etan/MTX (635 pt-yrs)
– 197 on MTX alone (388 pt-yrs)
• No malignancies seen to date
DODAC Meeting
June 18, 2008
18
Summary
Summary
•• TNF
TNF blockers
blockers as
as aa class
class have
have proven
proven highly
highly
effective
effective in
in variety
variety of
of autoimmune
autoimmune conditions
conditions
•• Use
Use of
of TNF
TNF blockers
blockers associated
associated with
with aa variety
variety of
of
uncommon
uncommon but
but serious
serious adverse
adverse events
events
•• Risk/benefit
Risk/benefit relationship
relationship favorable
favorable in
in approved
approved
indications
indications
•• In
In adults,
adults, evidence
evidence suggests
suggests that
that TNF
TNF blockers
blockers
may
may increase
increase risk
risk in
in patients
patients with
with underlying
underlying
elevated
elevated risk
risk of
of malignancy
malignancy
•• Recent
Recent reports
reports of
of malignancies
malignancies in
in children
children
receiving
receiving TNF
TNF blockers
blockers are
are of
of concern
concern and
and are
are
currently
currently under
under investigation
investigation
DODAC Meeting
June 18, 2008
19
DODAC Meeting
June 18, 2008
20
Post
-Marketing Adverse
Post-Marketing
Adverse Event
Event
Experience
Experience with
with Etanercept
Etanercept in
in
Children
Children aged
aged 44 to
to 17
17 years
years old
old
Hyon
Hyon (KC)
(KC) Kwon,
Kwon, Pharm.D.,
Pharm.D., M.P.H.
M.P.H.
Safety
Safety Evaluator
Evaluator
Division
Division of
of Adverse
Adverse Event
Event Analysis
Analysis II
Office
Office of
of Surveillance
Surveillance and
and Epidemiology
Epidemiology
June
June 18,
18, 2008
2008
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
Objective
Objective
• Inform the safety of etanercept for
use in pediatric plaque psoriasis
population
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
2
Outline
Outline
•• Background
Background
•• Drug
Drug Utilization
Utilization
•• Overview
Overview of
of Pediatric
Pediatric AERS
AERS Reports
Reports
•• Discussion
Discussion of
of Specific
Specific Post-Marketing
Post-Marketing
Adverse
Adverse Events
Events (Infections,
(Infections, Malignancies,
Malignancies,
Others)
Others)
•• Summary
Summary and
and Conclusion
Conclusion
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
3
Background
Background
•• Etanercept
Etanercept is
is aa tumor
tumor necrosis
necrosis factor
factor
(TNF)
(TNF) blocker
blocker
•• Etanercept
Etanercept is
is one
one of
of four
four TNF
TNF blockers
blockers
[infliximab,
[infliximab, adalimumab,
adalimumab, certolizumab]
certolizumab]
approved
approved for
for treatment
treatment of
of various
various
inflammatory
inflammatory diseases
diseases
•• What
What we
we know
know about
about the
the post-marketing
post-marketing
safety
safety profile
profile of
of etanercept
etanercept has
has largely
largely
come
come from
from the
the use
use of
of this
this and
and other
other TNF
TNF
blockers
blockers in
in adults
adults (multiple
(multiple indications)
indications)
and
and children
children with
with JIA
JIA
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
4
Adverse
Adverse Event
Event Reporting
Reporting System
System
(AERS)
(AERS)
•• Computerized
Computerized database
database of
of Adverse
Adverse Event
Event
Reports
Reports
•• Strengths:
Strengths:
–– Detection
Detection of
of events
events not
not seen
seen in
in clinical
clinical trials
trials
–– Especially
Especially good
good for
for events
events with
with rare
rare
background
background rate,
rate, short
short latency
latency
•• Limitations:
Limitations:
–– Underreporting,
Underreporting, variable
variable quality
quality of
of reporting
reporting
–– Reporting
Reporting biases
biases
–– Actual
Actual numerator
numerator &
& denominator
denominator not
not known
known
–– Difficult
Difficult to
to attribute
attribute events
events with
with high
high
background
background rate,
rate, long
long latency
latency
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
5
Etanercept
Etanercept Drug
Drug Utilization:
Utilization: Projected
Projected Number
Number
of
of Patients
Patients in
in U.S.
U.S. Outpatient
Outpatient Retail
Retail Pharmacies
Pharmacies
Number of Patients
160,000
160,000
140,000
140,000
120,000
120,000
100,000
100,000
80,000
80,000
60,000
60,000
40,000
40,000
20,000
20,000
1955
4301
00
2002
2002
2003
2003
2004
2004
2005
2005
2006
2006
2007
2007
Year
Year
Source: Verispan Total Patient Tracker
All
All ages
ages
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
4-17yrs
4-17yrs
6
Etanercept
Etanercept Drug
Drug Utilization
Utilization
•• Rheumatologists
Rheumatologists the
the most
most common
common prescribers
prescribers
~59%
~59% of
of Y2007
Y2007 prescriptions*
prescriptions*
•• Dermatologists
Dermatologists had
had largest
largest increaseincrease- 3,000
3,000 Rx
Rx in
in
Y2002
Y2002 to
to 104,000
104,000 in
in Y2007
Y2007 (~13%
(~13% of
of Y2007
Y2007
prescriptions)*
prescriptions)*
•• Most
Most common
common indications
indications for
for use
use in
in children
children
were
were polyarthritis
polyarthritis and
and psoriasis
psoriasis (off-label
(off-label use)**
use)**
Source:
Source: *Verispan,
*Verispan, Vector
Vector One:
One: National.
National. **Verispan
**Verispan Physician
Physician Drug
Drug and
and Diagnosis
Diagnosis Audit
Audit
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
7
Overview
Overview of
of Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Reports*:
Reports*:
1998
1998 to
to April
April 14,
14, 2008
2008
Number of reports
949
[Total Etanercept AERS reports =
54,710]
Gender:
Female
Male
Not reported
Median age
Report source:
US
Foreign
Not reported
677 (71%)
254 (27%)
18 (2%)
13 years
711 (75%)
219 (23%)
19 (2%)
*crude data, duplicates not reconciled
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
8
Overview
Overview of
of Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Reports*:
Reports*:
1998
1998 to
to April
April 14,
14, 2008
2008
Most Commonly Reported Indications:
JIA
Rheumatoid arthritis
Psoriasis
Psoriatic arthropathy/arthritis
Ankylosing spondylitis
Psoriasis Subset:
US
Foreign
Most Serious Outcome - Hospitalization
592 (62%)
71 (7%)
61 (6%)
47 (5%)
26 (3%)
61
59
2
5
*crude data, duplicates not reconciled
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
9
Overview
Overview of
of Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Reports:
Reports:
1998
1998 to
to April
April 14,
14, 2008
2008
Outcomes:
Death
Hospitalizations [HO]
Life-threatening [LT]
Required intervention
Others
14 unique cases
200*
6*
3*
708*
*crude data, duplicates not reconciled
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
10
Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases:
Cases:
Reporting
death’ (N=14)
Reporting an
an outcome
outcome of
of ‘‘death’
(N=14)
Indications:
JIA
IPS
GVHD
Unknown
8
3
2
1
Reported causes of death in
JIA cases (N=8):
Infections
Cardiac
Liver failure
Immunodeficiency
Unknown
4
1
1
1
1
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
11
Case
death’
Case with
with an
an outcome
outcome of
of ‘‘death’
due
due to
to infection
infection
A
A 17-year-old
17-year-old girl
girl received
received etanercept
etanercept 25
25
mg
mg twice
twice weekly
weekly for
for treatment
treatment of
of JIA,
JIA, and
and
died
died due
due to
to pneumococcal
pneumococcal meningitis.
meningitis.
Her
Her concomitant
concomitant medications
medications included
included
MTX.
MTX. After
After an
an unknown
unknown time
time on
on
etanercept,
etanercept, she
she presented
presented to
to the
the ER
ER with
with aa
3-day
3-day history
history of
of fever
fever and
and mental
mental status
status
changes.
changes. The
The CSF
CSF culture
culture was
was positive
positive
for
for strep
strep pneumoniae.
pneumoniae. She
She developed
developed
cerebral
cerebral edema,
edema, increased
increased intracranial
intracranial
pressure,
pressure, and
and brain
brain death.
death.
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
12
U.S.
U.S. Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases
Cases
Reporting
Reporting Serious
Serious [HO,
[HO, LT]
LT] Infections
Infections
(N
(N == 31)
31)
••
••
••
••
••
••
••
••
Respiratory
Respiratory tract
tract infections
infections (5)
(5)
Abscesses
Abscesses (4)
(4)
Urinary
Urinary tract
tract infections
infections (4)
(4)
Sepsis/Septic
Sepsis/Septic shock
shock (3)
(3)
Osteomyelitis
Osteomyelitis (2)
(2)
Cellulitis
Cellulitis (2)
(2)
Ear
Ear infections
infections (2)
(2)
Other:
Other: Systemic
Systemic histoplasmosis
histoplasmosis (1),
(1),
sinusitis
sinusitis (1),
(1), streptococcal
streptococcal throat
throat
infections
infections (1),
(1), Staphylococcal
Staphylococcal toxic
toxic shock
shock
syndrome
syndrome (1),
(1), flu
flu syndrome
syndrome (1),
(1),
conjunctivitis
conjunctivitis (1),
(1), unspecified
unspecified (3)
(3)
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
13
U.S.
U.S. Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases
Cases
Reporting
Reporting Serious
Serious [HO,
[HO, LT]
LT] Infections
Infections
(N
(N == 31)
31)
Gender:
Female
Male
24
7
Median Age
Reported dose (N=20)
Median
Range
Onset (N=25):
Median
Range
Concomitant use of other
immunosuppressants
12 years
25 mg twice weekly (0.4 mg/kg)
8 mg twice weekly - 50 mg/weekly,
(0.2 - 0.66 mg/kg/dose)
8 month
1 day - 4 years
22
(reported as co-suspects in 2)
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
14
Cases
Cases of
of Serious
Serious Infection
Infection
•• A
A 8-year-old
8-year-old girl
girl was
was hospitalized
hospitalized with
with
Staph
Staph aureus
aureus osteomyelitis
osteomyelitis after
after receiving
receiving
etanercept
etanercept therapy
therapy for
for JIA.
JIA. Etanercept
Etanercept
was
was discontinued
discontinued and
and the
the infection
infection was
was
treated.
treated.
•• A
A 16-year-old
16-year-old girl
girl was
was hospitalized
hospitalized with
with
systemic
systemic fungal
fungal infection
infection thought
thought to
to be
be
histoplasmosis
histoplasmosis after
after about
about 6.5
6.5 months
months of
of
etanercept
etanercept therapy
therapy for
for JIA.
JIA. Her
Her
concomitant
concomitant medication
medication included
included MTX.
MTX.
Liver
Liver and
and lung
lung biopsy
biopsy revealed
revealed systemic
systemic
fungal
fungal infection.
infection. She
She improved
improved with
with
amphotericin
amphotericin treatment.
treatment.
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
15
Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases:
Cases:
Other
Other Associated
Associated Infections
Infections
• Varicella (N=10)
–– Six
Six cases
cases resulted
resulted in
in hospitalizations
hospitalizations
–– Two
Two cases
cases appear
appear to
to be
be primary
primary
infections,
infections, and
and two
two cases
cases appear
appear to
to be
be
reactivations
reactivations
• Tuberculosis (N=2)
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
16
Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases:
Cases:
Malignancies
Malignancies (N
(N == 12*)
12*)
• B-cell lymphoma (2), Hodgkin’s
lymphoma (1), malignant lymphoma
& acute myeloid leukemia (1)
• Acute lymphocytic leukemia (2),
unspecified leukemia (1)
• Myelodysplastic syndrome (1)
• Papillary thyroid cancer (1)
• Malignant melanoma (1)
• Bladder cancer (1)
• Yolk sac tumor, site unspecified (1)
*9 cases from May 2008 OSE Review; 3 additional cases subsequently
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
17
Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases:
Cases:
Malignancies
Malignancies (N
(N == 12)
12)
Gender:
Female
Male
Unknown
5
5
2
Age at event onset (n=10):
Median
Range
17 years
10 - 19 years
Indications:
JIA
Ankylosing spondylitis
Unknown
Onset (N=9):
Median
Range
10
1
1
3 years
29 days - 7 years
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
18
Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases:
Cases:
Malignancies
Malignancies (N
(N == 12)
12)
Concomitant use of other
immunosuppressants
8
Serious outcomes:
Hospitalization
(+Life-threatening)
Reported doses (N=6)
6 (+2)
25 mg (5)
0.4 mg/kg (1)
Report source:
US
Foreign
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
5
7
19
Case
Case of
of Malignancy
Malignancy
A 15-year-old girl developed
Hodgkin’s lymphoma after receiving
Etanercept 22.5 mg twice weekly for
4.5 years and MTX 15 mg weekly for
3.6 years for treatment of
polyarticular JIA. Both drugs were
discontinued, and remission
occurred after chemotherapy.
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
20
Malignancy
Malignancy Risk
Risk in
in Children:
Children:
Ongoing
Ongoing Assessment
Assessment
• FDA currently investigating possible
association between the use of TNF
blockers and development of
malignancies in children
• FDA Early Communication issued on
June 3, 2008
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
21
U.S.
U.S. Etanercept
Etanercept Pediatric
Pediatric AERS
AERS Cases
Cases
Reporting
Reporting Other
Other Serious
Serious [HO,
[HO, LT]
LT] Events
Events
•• Neurologic
Neurologic Events
Events (N=10)
(N=10)
–– Seizures
Seizures (5)
(5)
–– Pseudotumor
Pseudotumor cerebri
cerebri (2)
(2)
–– Headaches
Headaches (2)
(2)
–– Multiple
Multiple sclerosis
sclerosis with
with optic
optic neuritis
neuritis (1)
(1)
•• Hematologic
Hematologic Events
Events (N=6)
(N=6)
–– Aplastic
Aplastic anemia
anemia (1)
(1)
–– Pancytopenia,
Pancytopenia, hemolytic
hemolytic anemia
anemia (1)
(1)
–– Leukopenia,
Leukopenia, anemia
anemia (1)
(1)
–– Neutropenia
Neutropenia (1)
(1)
–– Thrombocytopenia,
Thrombocytopenia, petechiae
petechiae (1)
(1)
–– Hemolysis,
Hemolysis, disseminated
disseminated intravascular
intravascular
coagulopathy
coagulopathy (1)
(1)
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
22
Etanercept
Etanercept Pediatric
Pediatric Adverse
Adverse Event:
Event:
Summary
Summary
•• Infections
Infections were
were the
the most
most commonly
commonly
reported
reported cause
cause of
of deaths
deaths and
and other
other
serious
serious outcomes
outcomes (hospitalizations,
(hospitalizations, lifelifethreatening)
threatening)
•• Potential
Potential long-term
long-term toxicities
toxicities such
such as
as
malignancies
malignancies are
are worrisome
worrisome in
in children
children
with
with plaque
plaque psoriasis
psoriasis
•• Current
Current etanercept
etanercept usage
usage in
in pediatric
pediatric
population
population is
is low
low
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
23
Etanercept
Etanercept Pediatric
Pediatric Adverse
Adverse Event:
Event:
Conclusion
Conclusion
•• Despite
Despite low
low etanercept
etanercept usage
usage in
in pediatric
pediatric
population,
population, we
we observed
observed similar
similar serious
serious
adverse
adverse events
events in
in children
children to
to those
those seen
seen
in
in adults
adults
•• The
The use
use of
of etanercept
etanercept therapy
therapy will
will likely
likely
place
place children
children with
with plaque
plaque psoriasis
psoriasis at
at aa
greater
greater risk
risk for
for developing
developing serious
serious
adverse
adverse events
events that
that are
are not
not usually
usually
observed
observed in
in this
this patient
patient population
population
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
24
Acknowledgements
Acknowledgements
Mark
Mark Avigan,
Avigan, M.D.,
M.D., C.M.,
C.M., Director,
Director, DAEA
DAEA II ,, Office
Office of
of Surveillance
Surveillance &
&
Epidemiology
Epidemiology
Marilyn
Marilyn R.
R. Pitts,
Pitts, Pharm.D.,
Pharm.D., Safety
Safety Evaluator
Evaluator -- Team
Team Leader,
Leader, DAEA
DAEA I,I,
Office
Office of
of Surveillance
Surveillance &
& Epidemiology
Epidemiology
Allen
Allen Brinker,
Brinker, M.D.,
M.D., MPH,
MPH, Epidemiologist
Epidemiologist -- Team
Team Leader,
Leader, DEPI,
DEPI, Office
Office
of
of Surveillance
Surveillance &
& Epidemiology
Epidemiology
Dave
Dave Moeny,
Moeny, R.Ph.,
R.Ph., USPHS,
USPHS, Drug
Drug Use
Use Specialist,
Specialist, DEPI,
DEPI, Office
Office of
of
Surveillance
Surveillance &
& Epidemiology
Epidemiology
Jeff
Jeff N.
N. Siegel,
Siegel, M.D.,
M.D., Medical
Medical Officer
Officer -- Team
Team Leader,
Leader, DAARP,
DAARP, ODE
ODE IIII
Division
Division of
of Dermatology
Dermatology and
and Dental
Dental Products
Products
Pediatric
Pediatric and
and Maternal
Maternal Health
Health Staff
Staff
Office
Office of
of Drug
Drug Evaluation
Evaluation III
III
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
25
Back
-up slides
Back-up
slides
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
Amgen
’s Risk
Amgen’s
Risk Mitigation
Mitigation Proposal
Proposal
• Proposed activities targeted to pediatric
plaque psoriasis indication
Labeling
Labeling
•• Medication
Medication Guide
Guide
Education
Education
•• Healthcare
Healthcare providers
providers
•• Routine
Routine educational
educational efforts
efforts (e.g.,
(e.g., CME,
CME, educational
educational
presentations,
presentations, dissemination
dissemination of
of safety
safety information)
information)
•• Prescriber
Prescriber checklist
checklist
•• Appropriate
Appropriate patient
patient selected
selected based
based on
on indication
indication
•• Immunizations
Immunizations completed
completed
•• Tuberculosis
Tuberculosis and
and hepatitis
hepatitis B
B screening
screening completed
completed
•• Starter
Starter kit
kit to
to provide
provide to
to caregivers
caregivers and
and patients
patients
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
27
Challenge
Challenge with
with
Amgen
’s Risk
Amgen’s
Risk Mitigation
Mitigation Proposal
Proposal
• Educational efforts may not be enough
to mitigate the risks in the pediatric
plaque psoriasis population
Proposal
Proposal relies
relies on
on voluntary
voluntary prescriber
prescriber
compliance
compliance
Difficult
Difficult to
to measure
measure program’s
program’s impact
impact
adequately
adequately
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
28
Additional
Additional Risk
Risk Mitigation
Mitigation Options
Options
• Documentation of safe use for patients
to receive etanercept
Up-to-date
Up-to-date immunizations
immunizations
Screening
Screening for
for tuberculosis
tuberculosis and
and hepatitis
hepatitis
B
B
• Prescriber/Patient Agreement for
documentation of safe-use conditions
Required
Required patient
patient counseling
counseling
Receipt
Receipt of
of Medication
Medication Guide
Guide
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
29
Challenges
Challenges with
with Etanercept
Etanercept
Risk
Risk Mitigation
Mitigation in
in Pediatrics
Pediatrics
• Difficult to mitigate certain risks (e.g.,
malignancy, demyelinating disease,
growth-related risk)
Younger
Younger patient
patient populations
populations may
may incur
incur longerlongerterm
term exposure
exposure potentially
potentially increasing
increasing the
the risk
risk of
of
serious,
serious, life-threatening
life-threatening adverse
adverse events
events
In
In absence
absence of
of identified
identified risk
risk factors,
factors, mitigation
mitigation is
is
limited
limited to
to “appropriate
“appropriate patient
patient selection”
selection” based
based on
on
perceived
perceived risk:benefit
risk:benefit balance
balance
May
May be
be difficult
difficult to
to identify
identify appropriate
appropriate patient
patient
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
30
Challenges
Challenges with
with Additional
Additional Risk
Risk
Mitigation
Mitigation Options
Options
• Difficult to implement additional tools
to assure safe use to one population
when a product is approved for
multiple indications/populations
Confusion
Confusion likely
likely among
among prescribers
prescribers using
using
the
the product
product for
for other
other indications
indications
• Burdensome to healthcare practitioners
and patients
Mandatory
Mandatory enrollment
enrollment of
of prescribers
prescribers and
and
possibly
possibly patients
patients across
across all
all indications
indications
would
would be
be needed
needed
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
31
Serious
Serious Infections
Infections and
and Malignancy
Malignancy
Relative
Relative Risk
Risk in
in Adults
Adults
• Meta-analysis of RCTs in adults by
Bongartz et al (JAMA May 17, 2006)
– Infliximab and adalimumab
– 9 trials
•• 3,493
3,493 anti-TNF
anti-TNF therapy
therapy
•• 1,512
1,512 placebo
placebo
•• 6-12
6-12 months
months of
of exposure
exposure
–– Odds
Odds ratio
ratio for
for malignancy
malignancy ~3
~3
–– Odds
Odds ratio
ratio for
for serious
serious infection
infection ~2
~2
–– Unknown
Unknown ifif these
these risks
risks apply
apply to
to children
children
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
32
Malignancy
Malignancy
Controlled
Controlled versus
versus Observational
Observational Studies
Studies
• No increased risk seen in large
observational studies published to date
•• Setoguchi
Setoguchi et
et al,
al, Geborek
Geborek et
et al,
al,
Askling
Askling et
et al
al
• May have implications for postmarketing
(postapproval) risk assessment
•• What
What types
types of
of studies
studies are
are prudent?
prudent?
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
33
Serious
Serious Infections
Infections
Absolute
Absolute Risk
Risk
•• Controlled
Controlled data
data available
available from
from trial
trial
20030211
20030211
–– 210
210 exposures
exposures
–– Average
Average 9.4
9.4 months
months etanercept
etanercept exposure
exposure
–– 22 (~1%)
(~1%) patients
patients categorized
categorized with
with serious
serious
infections
infections
•• Expectation
Expectation for
for serious
serious infection
infection rate
rate in
in
general
general marketing
marketing to
to be
be ~1%
~1% given
given for
for
every
every 9.4
9.4 months
months of
of exposure
exposure
–– Relative
Relative risk
risk to
to population
population with
with disease
disease not
not known
known
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
34
160
5
5
4
4
3
3
2
2
1
1
0
Adult Patients (000)
140
120
100
80
60
40
20
0
2002 2003 2004 2005 2006 2007
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
Pediatric Patients (000)
Enbrel
® Drug
Enbrel®
Drug Utilization
Utilization Trends
Trends by
by
Age
Age Group
Group
18+
0-3
4 - 17
35
Drug
Drug Use
Use Limitations
Limitations
•• Retail
Retail pharmacies
pharmacies only
only account
account for
for 34-47%
34-47% of
of
yearly
yearly distribution*
distribution*
•• Primary
Primary distribution
distribution channel
channel in
in 2007
2007 was
was mail
mail
order
order which
which was
was not
not examined
examined
•• Due
Due to
to low
low pediatric
pediatric use,
use, unable
unable to
to examine
examine
diagnosis
diagnosis trends
trends
*Source:
*Source: IMS
IMS Health,
Health, IMS
IMS National
National Sales
Sales Perspectives
Perspectives
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
36
Enbrel
® Pediatric
Enbrel®
Pediatric Cases:
Cases:
Reporting
death’ (N=14)
Reporting an
an outcome
outcome of
of ‘‘death’
(N=14)
Gender:
Male
Female
8
6
Median Age
Reported dose (N=9)
Median
Range
Onset (N=11):
Median
Range
9.5 years
0.4 mg/kg
0.3 mg/kg - 0.8 mg/kg
1 month
1 day - 34 months
Report Source:
US
Foreign
Dermatologic and Ophthalmic Drugs Advisory Committee
June 18, 2008
7
7
37
Etanercept for Pediatric Psoriasis:
Benefit and Risk Considerations
Advisory Committee Meeting
June 18 , 2008
Hari Cheryl Sachs, MD, FAAP; Medical Officer
Pediatric and Maternal Health Staff
Office of New Drugs
Food and Drug Administration
1
Outline
• Current Etanercept Labeling
• Etanercept: Risks and Benefits
– Additional Pediatric Considerations
• Summary
2
Drug Information:
Current Etanercept Labeling
Approved Indications:
• Adult
– Ankylosing spondylitis
– Plaque psoriasis (moderate to severe) and psoriatic
arthritis
– Rheumatoid arthritis
• Pediatric
– Juvenile Idiopathic Arthritis (JIA) in children 2 years
and older
3
Product Labeling: Boxed Warning
Boxed warning:
– Serious infections leading to hospitalizations or
death
– Tuberculosis (disseminated or extra-pulmonary)
4
Product Labeling: Precautions
Precautions:
• General: anaphylaxis (less than 2%)
• Patients with Heart Failure: worsening or new CHF
• Immunosuppression
• Immunizations:
– Although mount effective B-cell response, pneumococcal
titers lower
– Not to receive live vaccines
– JIA patients brought “up to date” before initiating
– If exposed to varicella, discontinue etanercept; consider VZIG
• Autoimmunity
5
Product Labeling: Adverse Events
Adverse Events in Patients with JIA:
• Severe adverse reactions: varicella,
gastroenteritis, personality disorder, cutaneous
ulcer, esophagitis/gastritis, Group A
streptococcal septic shock, Type I diabetes, soft
tissue and post-op wound infection
• Infection: 43/69 (62%) of JIA patients in 3
month open label study
• More commonly in children than adults:
headache, nausea, abdominal pain, and vomiting
6
Risks: Additional FDA
Communication
• Early communication (June 2008):
lymphoma and other malignancies
associated with TNF blocker treatment of
JIA
7
Risks: Literature Reports
• Infection:
– Serious infections in registry (zoster, HSV, stomatitis,
cellulitis)
– Tuberculosis
– Case reports: mononucleosis, fungal skin infection,
Group A streptococcal osteomyelitis, septic arthritis,
Methicillin-resistant staphylococcal infection
• Malignancy:
– Case reports: thyroid cancer (10 year old)
• CNS/demyelination
– Case reports: aseptic meningitis, optic neuritis
8
Benefits: Pediatric Psoriasis Trial
During 12 week clinical trial, statistically significant
improvements from baseline observed for majority of
endpoints in treatment group compared with placebo
• Clear/almost clear sPGA (52 vs. 13%, p< 0.0001)
48% had residual disease
• PASI 75 (57 vs. 11%, p<0.0001)
>40% did not achieve a PASI 75
• PASI 90 (27 vs. 7%, p <0.0001)
>70% did not achieve a PASI 90
• PASI 100 (7 % vs. 2%)
> 90% did not achieve PASI 100
9
Trial Results
10
Benefits: Maintenance of Efficacy
(Randomized Withdrawal Phase)
11
Additional Considerations:
Pediatric Patients
• Vaccine response
– Labeling: live vaccines contraindicated, response
to pneumococcal vaccine attenuated
– No data on routine childhood or adolescent
immunizations
• Vaccine platform (age 4 to 6y): MMR, Varicella, DtaP,
IPV and if high risk: PPV, HAV, MCV4
• Vaccine platform (age 11 to 12y): HPV (females),
MCV4, Tdap, and if high risk: PPV, Influenza (LAIV),
HAV
12
Additional Considerations:
Pediatric Patients
• Growth
– Unknown
• Developing Immune System
– effects on the developing immune system are
unknown
• Other
– Long-term safety unknown
13
Summary
The Committee is asked to discuss the benefits and
risks of use of Etanercept in children with plaque
psoriasis, considering:
– Psoriasis may be sporadic and remitting, yet therapy
with etanercept is likely to be continuous
– Psoriasis is not life-threatening; however, therapy with
etanercept is associated with serious, life-threatening
adverse events including sepsis, tuberculosis and longterm complications such as malignancy and neurologic
events
– Risks of malignancy are unresolved and data continues
to accumulate
14
Acknowledgements
OSE
Mark Avigan, MD
Susan Berkman
Allen Brinker, MD
Peter Diak
KC Kwon, PharmD
Lauren Lee
Dave Moeny
Marilyn Pitts
Kendra Worthy
DAARP
Rosemary Neuner, MD
Jeff Siegel, MD
DDDP
David Kettl, MD
Markham Luke, MD PhD
Tamika White
PMHS
Lisa Mathis, MD
Denise Pica Branco
15
Back up Slides
16
Pharmaceutical Treatment Options:
Topical
• OTC products (coal tar and salicylic acid)
• Topical Steroids:
– Medium potency (e.g., fluocinonide, triamcinolone,
betamethasone valerate)
• Caution: children may have greater susceptibility to systemic toxicity
• May interfere with growth and development
• Limit use to lowest dose
– Higher potency steroids (e.g., betamethasone dipropionate,
clobetasol and halobetasol) approved in 12 years and older
• Tazarotene (topical retinoid): 12 years and older
• Calcipotriene with/without betamethasone: adults only
Note: although approved for other pediatric dermatologic
indications, not approved for psoriasis in any
population: tacrolimus, and pimecrolimus
17
Pharmaceutical Treatment
Options: Systemic
• Corticosteroids (adults and pediatric patients)
Adults only
• *Acitretin
• *Cyclosporine
• *Methotrexate
• Biologic products: alefacept, *adalimumab,
*etanercept, *infliximab and *efalizumab
*Boxed warnings
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Risk: Benefit in Healthy Pediatric
Population
• Rotashield:
– Benefit: >90% effective at reducing
hospitalizations due to rotavirus gastroenteritis
– Risk: intussusception (1 case/10,000 doses)
Action: withdrawn from the market
• Oral polio vaccine
– Benefit: >95% develop life-long immunity after 3
doses of vaccine
– Risk: paralysis (one case in 750,000 to 1.2 million
doses)
Action: replace with inactivated polio vaccine
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