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Transcript of Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts...
Critical Issues for Bipolar Disorder
Gary S. Sachs, M.D.Harvard Medical School
Massachusetts General Hospital
October 25, 2005
Psychopharmocological Drugs Advisory Committee
Treatments for Chronic Mental Illness:Principles
1. Approval standards should reflect the interest of patients
2. Research design should be informed by clinical epidemiology
3. The best design methodology is that which optimizes validity and feasibility
Bipolar Disorder: Bipolar Disorder: Untreated vs TreatedUntreated vs TreatedStandardized Mortality RatiosStandardized Mortality Ratios
Bipolar Disorder: Bipolar Disorder: Untreated vs TreatedUntreated vs TreatedStandardized Mortality RatiosStandardized Mortality Ratios
Neoplasm Cardio-vascular
Cerebro-vascular
Accidents Suicide Other All Causes
UntreatedTreated
29.2*
6.4
1.4*0.6
2.2*1.7 1.6†
1.3 1.62.0 2.0*1.3
2.2*1.3
* p< 0.001 † p< 0.05
Zurich Cohort, n=4061959-1997
Adapted from
Angst, 2000
Should approval for an acute indication include a requirement for demonstration of
long-term efficacy?
• The Public Health interest is not served by establishing this requirement
• A policy intended to protect patients against acutely efficacious treatments without proven long-term benefit would benefit few, while depriving many of potentially helpful treatments
Is there a need to protect patients from treatments only proven to have short-term efficacy?
• Patients remain on ineffective medications briefly
• Effective medications are frequently discontinued over relatively short time periods
• Most patients using medications long-term are those who responded acutely and either perceive continued benefit or have suffered recurrence when attempting to taper.
Based on Altshuler et al. AJP.
2003
Discontinues afteracute response
Lack of efficacy
Continues long-termtreatment
Few get long-term treatment in the real world
Lithium Use and Discontinuation in a Health Maintenance Organization
Length of first continuous period of Lithium use (n=1594)Days
Lithium under used- only 8% used Li for 90% of days enrolled- median continuous use = 76 days
Adapted from: Johnson, Am J Psychi 1996100%
50%
20%
10%
30%
40%
60%
70%
80%
90%
0 500 1000 1500 2000
Principles of Current Clinical Practice• Bipolar disorder is a life long condition in which acute
episodes are separated by period of variable remission
• The episodic nature of bipolar disorder provides the organizing principle of treatment– Episodes are the target of acute and prophylactic treatment– Multiphase Treatment model
• Acute, Continuation, Maintenance/Discontinuation• Maintenance phase treatment reflects prior acute phase experience
Multiphase Treatment StrategyMultiphase Treatment Strategy
RecoveringRecovering RecoveredRecovered
Natural Course
Eu
thym
icD
epressed
Start Tx
AcuteMaintenance / DiscontinuationContinuationContinuation
Treated Course
Measurement
Basic Treatment paradigm is iterativeCritical
decision point
Intervention Intervention
Menu of reasonable choices
Option AOption AOption BOption BOption COption C
€€€€€€€€$$$$$$$$££££££££
++++++++++
++++++
Evidence Evidence A-FA-F
Individual factorsIndividual factors
Benefit: Adverse Effect + Cost
Each treatment trial is evaluated for
Iterative Process: Individual Response Directs Treatment Iterative Process: Individual Response Directs Treatment
Benefit
adverse effects
+ expense
None Fair Good Excellent
NoneMildModerate
Severe
+ +?
?? ? ?
? ?
? ?
Acuteepisode
Recovery
Maintenance Therapies in Bipolar Disorder Study Design
4 wks average •HRSD <7 &• Bech-Rafaelsen <7
Patient and family attend psychoeducational workshop
Weekly Acute treatment
RecoveryICM + protocol
pharmacotherapy
IPSRT + protocol pharmacotherapy
IPSRT + protocol pharmacotherapy
ICM + protocol pharmacotherapy
IPSRT + protocol pharmacotherapy
IPSRT + protocol pharmacotherapy
Preventative tx bi-weekly x 12 weeksthen monthly x 2 years
Relationship of TreatmentAssignment to Time to Recurrence
(n = 82)
Weeks to Recurrence in Preventative Phase0 10 20 30 40 50
Su
rviv
al D
istr
ibu
tio
n F
un
cti
on
0.0
0.2
0.4
0.6
0.8
1.0
ICM/ICMIPSRT/IPSRTICM/IPSRTIPSRT/ICM
* p = .03
*
Frank et al., Journal of Abnormal Psychology, in press
How well do our current treatments work?• Acute Bipolar depression
– No single agent has FDA approval for treatment of BP depression– STEP-BD and Altshuler/StanleyFBN data indicates need for
more efficacious treatments.
• Acute mania (8 approved agents)– The data from 3-4 week double blind trials indicates that on
average participants receiving active treatment finish the study with symptom severity scale scores above the severity score required for study entry.
• Prophylaxis (4 approved agents)– None consistently efficacious for all relevant outcome variables– None shown effective for subjects remaining well longer than 6
months
Acute Bipolar Depression:Acute Bipolar Depression:Placebo controlled therapy TrialsPlacebo controlled therapy Trials
with adequate* sample sizewith adequate* sample size
Acute Bipolar Depression:Acute Bipolar Depression:Placebo controlled therapy TrialsPlacebo controlled therapy Trials
with adequate* sample sizewith adequate* sample size
PositivePositivePositivePositive
Li+ ParoxetineLi+ ParoxetineLi+ ImipramineLi+ Imipramine
*power to detect a difference > 0.8
combinationcombination
LamotrigineLamotrigine
OlanzapineOlanzapine
QuetiapineQuetiapine
NegativeNegativeoror
FailedFailed
Olanzapine + Fluox.Olanzapine + Fluox.
monotherapymonotherapy
ImipramineImipramine
Placebo-Controlled Bipolar Depression Studieswith Adequate Samples
0 1 2 3 4 5 6 7
Week
PBO n=65LTG 50mg/day n=64LTG 200mg/day n=63
**
****
**
*
-20
-15
-10
-5
0
0 1 2 3 4 5 6 7 8Week
Chan
ge fr
om B
aseli
ne
PBO n=355OLZ n=351OFC n=82
*
**
**
*
*
****
*
Tohen et al.Calabrese et al.
*p<0.05 vs. PBO
OFC-olanzapine fluoxetine combination. Montgomery Asberg Depression Rating Scale.Calabrese et al. J Clin Psychiatry. 1999. Tohen et al. APA. 2002.
Calabrese et al
Calabrese et al APA 2004;
-20
-15
-10
-5
0
0 1 2 3 4 5 6 7 8
Seroquel 600mg/daySeroquel 300mg/dayPlacebo
*
*
*
* * * * *
*
**
* * * * *
MA
DR
SM
AD
RS
Ch
ang
e F
rom
Bas
elin
eC
han
ge
Fro
m B
asel
ine
16
A rough metric of clinical effectiveness: CE= Response Rate x Completion Rate
Study Response rate Completion rate CE NNT
OlZ = 39.0%OFC = 56.1%Placebo = 30.4%
QTP 300 = 58.2%QTP 600 = 57.6%Placebo = 36.1%
Calabrese1999
Calabrese 2005
Tohen 2003
48.4%64.0%38.5%
66.9%54.4%59.1%
18.9%35.9%11.7%
38.9%31.3%21.3%
5.710.0
13.94.1
65.0%71.0%71.0%
LTG 50 = 41%LTG 200 = 51%Placebo = 29%
26.7%36.2%20.6%
16.46.4
Real World Pharmaco-epidemologyNew treatment starts at MGH Bipolar Clinic
162
59%
166
47%
197
67%
97
53%
99
54%
127
57%
Lithium (n=49)
Valproate (n=38)
Lamotrigine(n=89)
AtypicalAntipsychotics
(n=216)
Antidepressants(n=264)
Anxiolytics(n=93)
Median tx duration (in days) % Recovered/Recovering
Majority use < 6 months
N =466 with at least 4 visits in year
Clinical intent to treat Bipolar Depression
1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
0.00.000 88 1616 2424 3232 4040 4848
Number of Weeks Until RelapseNumber of Weeks Until Relapse
Medication continuation groupMedication continuation groupMedication discontinuation groupMedication discontinuation group
Altshuler et al. AJP. 2003
N=1,078
84
15% remitted15% remitted
Acute Phase Maintenance PhaseResults from Stanley Foundation Bipolar Network
What is the benefit of standard antidepressants?Enriched sample of 84 Remitters = 15% of total84 Remitters = 15% of total
Adapted from Altshuler et al. AJP. 2003.
~ 25% relapse < 4 months ~ 25% relapse < 4 months onon or or offoff antidepressant antidepressant
~ 41% relapse 12 months ~ 41% relapse 12 months onon antidepressant antidepressant
~ 71% relapse < 4 months ~ 71% relapse < 4 months offoff antidepressant antidepressant
15%
11%
9%
4%
Ever 4 months 12 months usingAntidepressant
% Remaining Well> 1 year
Discontinued usingAntidepressant <6 months
12m -AD
STEP-BD Naturalistic data also indicatesgreat need for better acute treatments
0 40 80 120 160 200 240 280 320 360Days Well
15
10
5
0
Per
cent
Days well after reaching “Recovered”
Status(8 Wks Well)
MajorityMajorityhave remissionhave remission
< 6 months< 6 months
Acute Phase Maintenance Phase
2000 BP Subjects
377 Intent to treat Acute depression
Outcome at 90 Days% recovered
With AD = 21.5%No Ad = 27.2%
Median 96.5
Psychiatric patients need more acute treatments
• The proportion of patients achieving an acute benefit is modest
• There is a compelling need for more acutely efficacious medications
• Raising the bar to require long-term efficacy is not yet practical
• Limiting patient choice to only new treatments with proven long-term efficacy will leave potential responders untreated or seeking options unavailable here
Less than 10% will benefitLess than 10% will benefitLess than 10% will benefitLess than 10% will benefit• The proportion meeting criteria for response or remission in most The proportion meeting criteria for response or remission in most
pivotal trial overstates the benefit of acute treatmentpivotal trial overstates the benefit of acute treatment• The proportion depressed meeting DSM-IV criteria for recovered is The proportion depressed meeting DSM-IV criteria for recovered is
modest (<20%)modest (<20%)• Among those achieving recovery, > 50% experience a recurrence Among those achieving recovery, > 50% experience a recurrence
within 3 monthswithin 3 months
• The vast majority will be negatively impactedThe vast majority will be negatively impacted by virtue of not having access to acutely beneficial treatmentsby virtue of not having access to acutely beneficial treatments
Is the Public Health interest well served by requiring demonstration of long term
efficacy at time of registration?
• No compelling benefit – The proportion of patients achieving an acute benefit is modest
– There is no surplus of acutely efficacious medications
– Patients usually stop ineffective medications quickly
– Even effective medications are discontinued over relatively short time periods
• New obstacles to approval of treatments with acute efficacy will harm patients
Critical Design Issues in Conducting Long-Term Trials in
Bipolar Disorder
Gary S. Sachs, M.D.Harvard Medical School
Massachusetts General Hospital
October 25, 2005
Psychopharmocological Drugs Advisory Committee
Relapse Study Design – Stabilization PeriodRelapse Study Design – Stabilization Period
Design Should Reflect Validity & Feasibility
• DSM-IV defines recovery from a mood episode as 8 weeks well• New proposal calls for 6 months for all chronic conditions• EU guidelines are condition dependent: 2 – 6 months• Data suggests one duration does not fit all conditions• The design should reflect clinical epidemiology of each condition• Successful studies use enriched designs• Study designed to enrich with atypical patients can be misleading
Stabilization Period – EU Guidelines
Flexibility Depending on Condition
Disorder Stabilization Period Major Depressive Disorder 8 – 12 weeks
Schizophrenia > 6 weeks
Manic Episode
Bipolar Depression
9 weeks
12 – 26 weeks
Generalized Anxiety Disorder 8 – 26 weeks
Panic Disorder 8 – 12 weeks
Obsessive Compulsive Disorder > 26 weeks
Social Anxiety Disorder 8 – 12 weeks
STEP – BD Data Time to Relapse and Roughening after Recovery
RougheningRoughening
Full EpisodeFull Episode
00 5050 100100 150150 200200 250250 300300 350350 400400Time to Event/CensoringTime to Event/Censoring
1.001.00
0.750.75
0.500.50
0.250.25
0.000.00
Su
rviv
al D
istr
ibu
tion
Fu
nct
ion
Su
rviv
al D
istr
ibu
tion
Fu
nct
ion Steady gradual slope
( 8 weeks stable remission)( 8 weeks stable remission)
(Days).
Placebo vs Olanzapine in Combination with Lithium or Valproate
% R
emai
ning
in R
emis
sion
0 100 200 300 400 500
0
20
40
60
80
100
p=.023
Time to Recurrence Into Mania or Depression
OLZ plus Li or VPA, (n=30)Li or VPA, (n=38)
Immediate steep slope
Randomized after symptomatic Randomized after symptomatic remission of mania (YMRS remission of mania (YMRS 12) and depression Ham-D 12) and depression Ham-D 8 8
Tohen et al. Poster presented at XXIII Congress of CINP; 2002; Montreal, QuebecTohen et al. Poster presented at XXIII Congress of CINP; 2002; Montreal, Quebec..
Time to Recurrence (Days)Time to Recurrence (Days)00 100100 200200 300300 400400 500500
Lithium or valproate, n=48Lithium or valproate, n=48
Olanzapine plus lithium or valproate, n=46Olanzapine plus lithium or valproate, n=46
Time to recurrence of mania after symptomatic Time to recurrence of mania after symptomatic remission of mania (YMRS remission of mania (YMRS 12)12)
P=0.005
Pro
bab
ility
of R
em
ain
ing
Pro
bab
ility
of R
em
ain
ing
in R
em
issi
on
(%)
in R
em
issi
on
(%)
0%
20%
40%
60%
80%
100%
Placebo vs Olanzapine in Combination with Lithium or Valproate
Immediate steep slope
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 30 40 50 60 70Week
Su
rviv
al E
stim
ate
PBO (n=119)
LTG200/400 (n=165)
Li (n=120)
2nd Lamotrigine Maintenance Study*
LTG v. PBO, p = 0.029Li v. PBO, p = 0.029LTG v. Li, p = 0.915
Randomized subjects well on monotherapy 1 week Randomized subjects well on monotherapy 1 week
Immediate steep slope
Relapse* Following Open, Prospective Non-Random Antidepressant Discontinuation vs. Continuation
53 BPI 24 BPII53 BPI 24 BPII1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
0.00.000 88 1616 2424 3232 4040 4848
Number of Weeks Until RelapseNumber of Weeks Until Relapse
Medication continuation groupMedication continuation groupMedication discontinuation groupMedication discontinuation group
* Relapse = CGI-S 4Altshuler et al. AJP. 2003
Steady gradual slope
Enriched Sample of 84 Remitters Enriched Sample of 84 Remitters 6 weeks CGI-S 6 weeks CGI-S 2 2
Aripiprazole Maintenance of Stability in Bipolar Mania
Aripiprazole
Placebo
Required 6 Weeks Well for RandomizationRequired 6 Weeks Well for Randomization
0.4
0.6
0.7
0.8
0.9
1.0
0.5
0 14 25 42 55 70 84 95 112 125 140 154 168 182 195 210
Relative risk = 0.523 (0.30, 0.913). Data on file, Otsuka America Pharmaceutical, Inc.
Days
Pro
por
tion
of
Pat
ien
ts W
ith
out
Rel
apse
Log-rank P value 0.020
Steady gradual slope
Successful studies use enriched designs
Total Entering
Study
Acute Phase“Responders”
=
ProportionRandomized
Lithium
65%
49% 49%
28%
15%
Valproate LTG-P Olanzapine Aripip M SFBN
Primary outcome NSPrimary outcome NSPrimary outcome positivePrimary outcome positive
Enrichment MostMostLeastLeast
Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design Problem• Conservative Assumptions – Great Obstacles to FeasibilityConservative Assumptions – Great Obstacles to Feasibility
•Eligibility Criteria for Randomization = “Responder”True Responder /All meeting response criteria = 50%
Assumes Response for Active = 50% Placebo = 25%
•“Enriched Sample” is a composite of 50% True Responders50% Pseudo Responders
In the Double blind Phase: Pseudo Responder Relapse Rates
Placebo = Active
Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemStudy Powered for relapse rate Study Powered for relapse rate
Placebo = 60% vs Active 40%Placebo = 60% vs Active 40%
“Enriched Sample” N=200 50% True Responders 50% Pseudo Responders
Placebo Cell n=100 50% True Responders50% Pseudo Responders
“Active Cell n=100
Subjects Subjects relapsingrelapsing
50 Pseudo Responders
50 TrueResponders
3030 1010 6060
Positive result requires active agent sustains effectiveness in at least 80%
Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemLonger stabilization phase: Longer stabilization phase:
Study Powered for relapse rate Study Powered for relapse rate Placebo = 40% vs Active 20%Placebo = 40% vs Active 20%
“Enriched Sample” N=200 50% True Responders 50% Pseudo Responders
Placebo Cell n=100 50% True Responders50% Pseudo Responders
“Active Cell n=100
Subjects Subjects relapsingrelapsing
50 Pseudo Responders
50 TrueResponders
2020 00 4040
Positive result requires active agent sustains effectiveness in 100%
0 40 80 120 160 200 240 280 320 360Days Well
15
10
5
0
Per
cent
Days well after reaching “Recovered” Status
(8 Wks Well)
produces a sample unrepresentative of patients seeking treatment
Use of a 6 month stabilization
MajorityMajorityhave remissionhave remission
< 6 months< 6 months
Summary Statistics
Number of Obs 281N Missing 19N 262
Median 96.5Mean 116.57Std Deviation 83.21Mode 63Maximum 365Minimum 3.5
Narrows the separation
Limiting randomization to subjects 6 months willalter study results
Antidepressant Discontinuation vs. ContinuationConditional on 6 months well
Number of Weeks Until RelapseNumber of Weeks Until Relapse
Medication continuation groupMedication continuation groupMedication discontinuation groupMedication discontinuation group
1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
0.00.000 88 1616 2424 3232 4040 4848
Relationship of TreatmentAssignment to Time to Recurrence
(n = 82)
Weeks to Recurrence in Preventative Phase0 10 20 30 40 50
Su
rviv
al D
istr
ibu
tio
n F
un
cti
on
0.0
0.2
0.4
0.6
0.8
1.0
ICM/ICMIPSRT/IPSRTICM/IPSRTIPSRT/ICM
Frank et al., Journal of Abnormal Psychology
Consequence of 6 Month StabilizationConditional on
remaining well for 6 monthsOriginal curves after 6 months
Trial Design: Summary of IssuesValidity• One size does not fit all conditions• Data shows what got you well keeps you well• 8 wks well is adequate to achieve stabilization• 6 month stabilization produces sample
unrepresentative of patients seeking treatment• 6 month stabilization will make it difficult to
detect a true difference between a NME and placebo
Trial Design: Summary of Issues
Feasibility• 6 month stabilization will require a larger sample• Larger samples will increase enrollment phase 8-
24 month heightening rater drift and sample variability
• An increase in enrollment times will delay or prevent patient access to innovative new treatments
• This proposal is not in the best interest of patients