All individuals who are in a position to control the content of the educational activity courseactivity directors planning committee members staff teachers or authors of CME must disclose all relevant financial relationships they have with any commercial interests as well as the natur ID: 465096
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It is the policy of the University of Arkansas for Medical Sciences (UAMS) College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all provided or jointly provided educational activities. All individuals who are in a position to control the content of the educational activity (course/activity directors, planning committee members, staff, teachers, or authors of CME) must disclose all relevant financial relationships they have with any commercial interest(s) as well as the nature of the relationship. Financial relationships of the individual’s spouse or partner must also be disclosed, if the nature of the relationship could influence the objectivity of the individual in a position to control the content of the CME. The ACCME describes relevant financial relationships as those in any amount occurring within the past 12 months that create a conflict of interest. Individuals who refuse to disclose will be disqualified from participation in the development, management, presentation, or evaluation of the CME activity.
UAMS Disclosure PolicySlide2
DisclosuresThe following planners and speaker of this CME activity has no relevant financial relationships with commercial interests to disclose: Lawrence Amsel, M.D.Suzanne Reiss, M.D.Diane Bloomfield, M.D.Mark Riddle, M.D.Cathryn Galanter, M.D.Jyoti Bhagia, M.D.
Harlan Gephart, M.D.Ruth Stein, M.D.Peter Jensen, M.D.Mark Wolraich, M.D.Robert Kowatch, M.D.Rachel Zuckerbrot, M.D.Rachel Lynch, M.D.
Elena Man,
M.D.Slide3
DisclosuresThe following planner and speaker of this CME activity has financial relationships with commercial interests to disclose: Laurence Greenhill, M.D.Bio BDX – Scientific Advisory BoardSlide4
Understanding the FDA Boxed WarningSlide5
Hidden Slide: Time TableTotal time: 25 minutesIntro/Goals and Objectives: 2’Safety and efficacy of antidepressant use in children and adolescents: 14’Discuss clinical recommendations for the use of antidepressant use in children and adolescents: 7’Summary/wrap up: 2’Point out handouts at back of section:SSRI letter for parentsAssessing suicide risk for providersSuicide prevention for parents
5
Unit F: Understanding the
FDA Boxed WarningSlide6
Learning ObjectivesReview the data that led to the FDA’s Boxed Warning for SSRIsDescribe safety and efficacy considerations of antidepressant use in children and adolescentsExplain clinical recommendations for the use of antidepressant use in children and adolescentsSlide7
HIDDEN SLIDENo more Black Box Warninghttp://healthjournalism.org/blog/2009/07/fda-rethinks-black-box-warning/FDA official wants media to stop using term ‘Black Box’ & just say ‘Boxed Warning.’ ‘Black Box carries implication ‘Don’t you dare use this.””Decision has to be made with family about the risk and benefit in using the drugs, and monitoring the patients closelySlide8
RESOURCE SLIDE:In the News…Aug2003
Wyeth: “…increased reports…of hostility and suicide-related adverse events.”
Oct
2003
FDA:
“
…data suggest an excess of (suicidality) reports
”
; plan for investigation of 8 antidepressants
British MHRA:
“
The majority of SSRIs… are not suitable to be used by under 18
’
s.
”
“
Risks…outweigh benefits….
”
Dec
2003
ACNP:
“
…several SSRI trials show efficacy…
”
;
“
…no statistically significant increases in suicidal behavior…
”
Jan
2004
Sep2004
Feb
2004
FDA: Plan for reclassification of each suicidal event.
FDA: Warnings to be placed on all antidepressants.
“
Black-box
”
warningSlide9
HIDDEN SLIDEThe next slide will deal with risk-benefit analysis.Utilize a child with a sore throat who comes into the office and has positive, rapid strep. Walk providers through analysis of giving IM PCN versus a prescription for oral antibiotics. 9
Unit F: Black Box WarningSlide10
How to Decide When to UseAny Medicine?Determine risksDetermine benefitsAssess risk-benefit ratioDiscuss risk-benefit relationship with patient and caregiversMonitor for adverse eventsKnown and unknownSlide11
BenefitsWhat “benefits” data did the FDA have at the time of the initial boxed warning?What “benefits” data has since emerged?Slide12
Pediatric Antidepressant UsesMood DisordersMajor Depressive DisorderPersistent Depressive DisorderBipolar DisorderOtherAnxiety DisordersGeneralized Anxiety DisorderObsessive Compulsive DisorderOtherOther second-line useAttention Deficit Hyperactivity DisorderOther (TCAs for enuresis, etc.)Slide13
Efficacy Data:Major Depressive DisorderFluoxetine receives FDA approval for child and adolescent depression in January 2003 after two positive randomized controlled trialsMany negative studies were unpublishedNIMH-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 efficacySlide14
Children
’
s Depression Rating Scale:
T
A
D
S
entry
responseSlide15
Efficacy Data:Major Depressive DisorderAfter 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) Slide16
Efficacy Data: Anxiety DisordersFDA approved fluoxetine, fluvoxamine, and sertraline for OCD in children and adolescents (prior to January 2003)RUPP Fluvoxamine (Luvox) study (2001) -> NEJMfluvoxamine >> plb in SAD: SocialAnxietyDisorder, GAD: Generalized Anxiety Disorder, SPh: Social PhobiaPittsburgh Anxiety Study - Birmaher et al. (2003) -> JAACAPfluoxetine > plb in SAD/GAD/SPhBrawman-Mintzer et al. (2006)Sertraline >(tiny difference) PBO in GADSlide17
Efficacy Data: Anxiety DisordersAfter the FDA Review:CAMS study (Walkup et al., 2008)Slide18
RisksWhat was known about safety and risks at the time of the FDA review?What has been learned since?Slide19
FDA Pooled AnalysesData pooled from 24 studiesPharmaceutical data (23 total studies)15 for MDD8 for other mental health disorders (obsessive-compulsive disorder, anxiety, ADHD)TADS (Treatment of Adolescent Depression) studySlide20
What Were Limitations of the Data?Majority of pharmaceutical studies were voluntarily done to obtain exclusivityStudies had small samples and were inadequately powered to detect a rare event like suicidalityStudies were of short duration (<16 weeks)Studies had selection bias due to variations in sample inclusionLess attention was paid to proceduresLimited uniformity across the studiesSlide21
Adverse Events: Data ProblemsFDA data was based on spontaneous reports, not a systematic suicide risk assessment done uniformly across studiesColumbia University needed to reclassify these events, although available data had significant limitations: Feb 2004Slide22
Results: Pooled DataSafetyRelative risk of suicidality (thoughts or behaviors) is 2.19 X greater for drug compared to placebo (95% CI 1.5-3.19); p-value=.00005Conclusion: Suicidality in these children did not occur by chance alone. There is a 2% risk in placebo and a 4% risk with medication: September 2004Slide23
Completed SuicideNo completed suicides in ANY of the acute studiesSlide24
Suicidality Improves Overall
T A D SSlide25
Suicide Ideation Questionnaire: Adjusted Means
T A D S
25
Unit F: Black Box WarningSlide26
The Role of Narratives inthe FDA HearingComparable to case reports (although missing data)NOT CAUSAL !Understand stakeholders’ perspectives (Scientology, lawsuits, etc.)***Many have said thatthe anecdotal reports significantly influenced the decision regarding the FDA’s boxed warningSlide27
2004 Black BoxWarning up to the age of 18Warned of increased suicidalityCalled for weekly visits for 4 weeks, every other week visits for another 8 weeks, and then monthly visitsSlide28
SSRIs and Suicide Slide29
FDA-Recommended Warning Boxand Close MonitoringIn 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.”Slide30
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.FDA-Recommended Warning Boxand Close MonitoringSlide31
The Risk-Benefit RatioSlide32
Pros and Cons to the Warning Box Pros Encourages consideration of risks/benefits before prescribingEncourages partnerships with familyEncourages exploration of all other available optionsMay result in more appropriate monitoring of patients Cons Increased Fear: patientsIncreased Fear: parentsIncreased Fear: prescribersSeriously impaired children may go untreatedChildren may be treated inappropriately with alternative medicationsSlide33
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 monitoringSlide34
Clinical RealitiesWe need to help anxious and depressed childrenSSRIs play a key role in several clinical scenarios: Partial response to psychotherapyLack of availability of resourcesImprove speed of responseSSRIs are effectiveBoth Fluoxetine & Escitalopram have several positive studies for MDD and have FDA approvalThree SSRIs with FDA approval for OCDSSRI data favorable for other Anxiety DisordersA risk-benefit ratio for one child may be different for anotherSlide35
Now What?Slide36
Summary: Clinical RecommendationsA careful assessment is criticalPartner 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 Slide37
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 comorbiditySlide38
Hidden SlidePoint out the handouts on suicide and SSRIs, suicide risk assessment, and safety planningMention that at the end of Unit H, the depression treatment unit, they will split into pairs to get experience performing safety planning with families and patients and discussing SSRIs and the black box F 1.1- 1.438
Unit F: Black Box WarningSlide39
REMINDER: Please fill out Unit F evaluationSlide40
NNT = 10
NNH = 112RESOURCE SLIDEPutting It Together: SSRI Risk vs. BenefitsMeta-Analysis, 27 Trials (published & unpublished)
Bridge et al. (JAMA 2007;18,297:1683-96)