Transcript Understanding the 2006 FDA Black Box Warning

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Disclosures
The following planners and speaker of this
CME activity has no relevant financial
relationships with commercial interests to
disclose:
•
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Lawrence Amsel, M.D.
Diane Bloomfield, M.D.
Cathryn Galanter, M.D.
Harlan Gephart, M.D.
Peter Jensen, M.D.
Robert Kowatch, M.D.
Rachel Lynch, M.D.
•
•
•
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•
Suzanne Reiss, M.D.
Mark Riddle, M.D.
Jyoti Bhagia, M.D.
Ruth Stein, M.D.
Mark Wolraich, M.D.
Rachel Zuckerbrot, M.D.
Elena Man, M.D.
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Disclosures
The following planner and speaker of this
CME activity has financial relationships with
commercial interests to disclose:
Laurence Greenhill, M.D.
– Bio BDX – Scientific Advisory Board
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Understanding the FDA
Boxed Warning
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Learning Objectives
• Review the data that led to the FDA’s Boxed
Warning for SSRIs
• Describe safety and efficacy considerations of
antidepressant use in children and adolescents
• Explain clinical recommendations for the use of
antidepressant use in children and adolescents
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RESOURCE SLIDE:
In the News…
Wyeth: “…increased
reports…of hostility
and suicide-related
adverse events.”
British MHRA: “The
majority of SSRIs…
are not suitable to be
used by under 18’s.”
“Risks…outweigh
benefits….”
Oct
2003
Aug
2003
FDA: “…data
suggest an excess of
(suicidality) reports”;
plan for investigation
of 8 antidepressants
FDA: Plan for
reclassification of
each suicidal event.
Jan
2004
Dec
2003
Sep
2004
Feb
2004
ACNP: “…several SSRI
trials show efficacy…”;
“…no statistically
significant increases in
suicidal behavior…”
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FDA: Warnings to
be placed on all
antidepressants.
“Black-box” warning
How to Decide When to Use
Any Medicine?
• Determine risks
• Determine benefits
• Assess risk-benefit ratio
• Discuss risk-benefit relationship with
patient and caregivers
• Monitor for adverse events
– Known and unknown
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Benefits
• What “benefits” data did the FDA have
at the time of the initial boxed warning?
• What “benefits” data has since
emerged?
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Pediatric Antidepressant Uses
• Mood Disorders
–
–
–
–
Major Depressive Disorder
Persistent Depressive Disorder
Bipolar Disorder
Other
• Anxiety Disorders
– Generalized Anxiety Disorder
– Obsessive Compulsive Disorder
– Other
• Other second-line use
– Attention Deficit Hyperactivity Disorder
– Other (TCAs for enuresis, etc.)
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Efficacy Data:
Major Depressive Disorder
• Fluoxetine receives FDA approval for child and
adolescent depression in January 2003 after two
positive randomized controlled trials
• Many negative studies were unpublished
• NIMH-funded study, treatment for adolescents
with depression study (TADS): large multi-site
trial on adolescent depression becomes
available (2004) and is our best gauge on
efficacy
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Children’s Depression Rating Scale:
Mean CDRS Score - Adjusted
60
COMB
50
FLX
CBT
PBO
entry
40
30
Baseline
response
Week 6
Week 12
Stage I Assessments
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TAD S
Efficacy Data:
Major Depressive Disorder
• After the FDA review:
– Escitalopram Studies (Wagner et al. 2006,
Emslie et al 2009)
– TORDIA Study (Brent et al. 2008)
– Escitalopram receives FDA approval for
MDD in 12 and up (2009)
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Efficacy Data: Anxiety Disorders
• FDA approved fluoxetine, fluvoxamine, and
sertraline for OCD in children and adolescents
(prior to January 2003)
• RUPP Fluvoxamine (Luvox) study (2001) -> NEJM
– fluvoxamine >> plb in SAD: SocialAnxietyDisorder, GAD:
Generalized Anxiety Disorder, SPh: Social Phobia
• Pittsburgh Anxiety Study - Birmaher et al. (2003) ->
JAACAP
– fluoxetine > plb in SAD/GAD/SPh
• Brawman-Mintzer et al. (2006)
– Sertraline >(tiny difference) PBO in GAD
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Efficacy Data: Anxiety
Disorders
• After the FDA Review:
– CAMS study (Walkup et al., 2008)
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Risks
• What was known about safety and risks
at the time of the FDA review?
• What has been learned since?
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FDA Pooled Analyses
• Data pooled from 24 studies
– Pharmaceutical data (23 total studies)
• 15 for MDD
• 8 for other mental health disorders (obsessivecompulsive disorder, anxiety, ADHD)
– TADS (Treatment of Adolescent Depression)
study
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What Were Limitations of the Data?
• Majority of pharmaceutical studies were
voluntarily done to obtain exclusivity
• Studies had small samples and were
inadequately powered to detect a rare event like
suicidality
• Studies were of short duration (<16 weeks)
• Studies had selection bias due to variations in
sample inclusion
• Less attention was paid to procedures
• Limited uniformity across the studies
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Adverse Events: Data Problems
• FDA data was based on spontaneous
reports, not a systematic suicide risk
assessment done uniformly across studies
• Columbia University needed to reclassify
these events, although available
data had significant limitations:
Feb 2004
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Results:
Pooled Data
• Safety
– Relative risk of suicidality (thoughts or behaviors)
is 2.19 X greater for drug compared to placebo
(95% CI 1.5-3.19); p-value=.00005
– Conclusion: Suicidality in these children did not
occur by chance alone. There is a 2% risk in
placebo and a 4% risk with medication:
September 2004
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Completed Suicide
• No completed suicides in ANY of the
acute studies
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Suicidality Improves Overall
30%
29.2%
27.0%
25%
20%
14.6%
15%
13.0%
11.6%
CDRS13 > 1
SIQ >= 31
10%
5%
2.7%
0%
Baseline
Week 6
Week 12
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TAD S
Suicide Ideation Questionnaire:
Adjusted Means
30
28
Mean Total Score
26
24
COMB
22
FLX
20
CBT
18
PBO
16
14
12
10
Baseline
Week 6
Week 12
Stage I Assessments
Unit F: Black Box Warning
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25
TAD S
The Role of Narratives in
the FDA Hearing
• Comparable to case reports
(although missing data)
• NOT CAUSAL !
• Understand stakeholders’
perspectives (Scientology, lawsuits,
etc.)
***Many have said that
the anecdotal reports significantly
influenced the decision regarding
the FDA’s boxed warning
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2004 Black Box
• Warning up to the age of 18
• Warned of increased suicidality
• Called for weekly visits for 4 weeks,
every other week visits for another 8
weeks, and then monthly visits
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SSRIs and Suicide
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FDA-Recommended Warning Box
and Close Monitoring
• In May 2007, the FDA ordered that all antidepressant medications
carry an expanded warning box with information re: increased risk
of suicidal symptoms in young adults 18-24 years of age
• “Antidepressants increased the risk of suicidal thinking and
behavior in children, adolescents, and young adults in short-term
studies with major depressive disorder (MDD) and other
psychiatric disorders. Short term studies did not show an increase
in the risk of suicidality with antidepressants compared to placebo
in adults beyond age 24, and there was a reduction in risk with
antidepressants compared to placebo in adults aged 65 and older.
This risk must be balanced with the clinical need. Monitor patients
closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need
for close observation and communication with the prescriber.”
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FDA-Recommended Warning Box
and Close Monitoring
• In the 2007 changes to the Warning Box, the FDA
discontinued its previous specific recommendations that C&A
starting an antidepressant be followed weekly x 4 weeks, then
q.o. week x 4 weeks, etc.
• NOTE: The Warning Box applies not just to antidepressants,
but to all drugs with similar mechanisms: e.g., atomoxetine
(SNRI approved for ADHD) has a Warning Box.
• Suicidality may occur with medications without a Warning Box,
i.e. even though stimulants are not officially “labeled” as linked
to suicidality, they can cause emotionality/over-arousal
that might in some vulnerable patients present as suicidality.
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The Risk-Benefit Ratio
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Pros and Cons to the Warning Box
Cons
Pros
• Encourages consideration
of risks/benefits before
prescribing
• Encourages partnerships
with family
• Encourages exploration
of all other available
options
• May result in more
appropriate monitoring of
patients
• Increased Fear: patients
• Increased Fear: parents
• Increased Fear:
prescribers
• Seriously impaired
children may go untreated
• Children may be treated
inappropriately with
alternative medications
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Interpretation
 SSRIs efficacious for depression, OCD, and non-OCD
anxiety. Benefits of SSRIs much greater than risks for
suicidality (Bridge et al., JAMA 2007:18,297:1683-96)
 Antidepressants may slightly increase rates of suicidal
“events” (thoughts, attempts). Given 2,000,000 events,
this is an important public health problem
 Antidepressants speed recovery and improve functional
outcomes, esp. if combined with CBT
 Antidepressants likely prevent death by suicide, probably
via effective treatment of depression
 Co-administered CBT may protect against suicidal events
and assists in monitoring
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Clinical Realities
• We need to help anxious and depressed children
• SSRIs play a key role in several clinical scenarios:
– Partial response to psychotherapy
– Lack of availability of resources
– Improve speed of response
– SSRIs are effective
• Both Fluoxetine & Escitalopram have several positive
studies for MDD and have FDA approval
• Three SSRIs with FDA approval for OCD
• SSRI data favorable for other Anxiety Disorders
• A risk-benefit ratio for one child may be different for
another
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Now What?
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Summary:
Clinical Recommendations
• A careful assessment is critical
• Partner with caregivers:
– Families and patients need to be fully
informed about the risks and benefits of
antidepressant treatment.
– Antidepressants should be initiated at a low
dose and titrated as indicated and tolerated
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Always Monitor:
• Treatment-emergent suicidality / Form a
Safety Plan with families (see F1.1-1.4)
• Sudden changes in mood or behaviour
• Compliance
• Adverse events
• Treatment emergent comorbidity
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REMINDER:
Please fill out Unit F
evaluation
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RESOURCE SLIDE
Putting It Together: SSRI Risk vs. Benefits
Meta-Analysis, 27 Trials (published & unpublished)
70%
61%
60%
50%
ADA
50%
PBO
40%
NNT = 10
30%
20%
NNH = 112
10%
3%
2%
0%
Response
Ideat/Attempt
Bridge et al. (JAMA 2007;18,297:1683-96)
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