The SAFER Interview• TheSAFERInterviewisanoperationalizedversionoftheSAFER(Specificity, Assessability, Face Validity, Ecological Validity, and Rule of the 3 Ps)principlesdevelopedbycliniciansatMassachusettsGeneralHospital(MGH)4.
• Inarecentanalysisoffivetrialsintreatmentresistantdepression(TRD)allsubjectshadpassedscreeningproceduresatthesiteandwereconsideredtobeeligibleforthetrial.
• Inadditiontothe45-minuteSAFERInterviewperformedremotelybyMGHclinicianswhocalledsubjects(N=1935)directly,astructuredseverityinterviewwasperformed;1562(81percent)ofthesubjectsweredeemedeligibleforcontinuedscreening.(Figure 5)
• Ofthe373(19percent)subjectsdeemedineligible:97(5percent)didnotmeetseveritycriteria;39(2percent)didnotmeetonlySAFERcriteria;151(8percent)didnotmeetATRQcriteriafortreatmentresistance;and,86(4percent)didnotmeetcriteriaonmorethanonecomponentoftheSAFERInterview.
• AcrossallofthesefiveTRDstudies,placeboresponserateswerewithinarangeof18to28percent,belowthe30to37percentaverageinstudiesoftreatmentsapprovedforTRD(olanzapine-fluoxetinecombination,quetiapineandaripiprazole).
Ziprasadone Monotherapy Study: Papakostas et al, J Clin Psychiatry. 2012 Dec; 73(12): 1541-7; TRD-1 and TRD-2: Papakostas et al, Am J Psychiatry. 2012 Dec 1; 169(12): 1267-74; ADAPT-A: Fava et al, Psychother Psychosom. 2012; 81(2): 87-97; Alkermes ALK 5461: Poster, ISCTM, 2013 Oct Note: ALK response rates relate to MADRS (secondary) outcomes.
19%
81%Zip Mono TRD-1 ADAPT-A TRD-2 ALK Average
12
68
54 52
81
53
100
80
60
40
20
0
% Reduction
Randomize
PlaceboActive
Treatment (Dose X)
Active Treatment
(Dose X)
Active Treatment
(Dose X)Placebo
ResponderResponderNon
ResponderNon
Responder
PlaceboActive
Treatment (Dose X)
Randomize
Randomize
TreatmentPhase 1
Results
TreatmentPhase 2
Rater Cohort Characteristics 1.00 80% 100
Experienced, calibrated 0.933 78% 108
0.80 71% 125
Inexperienced, calibrated 0.773 70% 130 0.60 59% 167
Experienced, calibrated 0.553 55% 181
Reliability (ICC) Study Power1 Sample Size per Arm2
Q1 Q2 Q3 Q4
HAM-A (N=100) (Study 1)* 0.90 0.96 0.95 0.97
HAM-A (N=68) (Study 2)* 0.98 0.97 0.97 0.96
PANSS (N=131) (Study 3)* 0.90 0.90 0.96 0.88
PANSS (N=67) (Study 4)* 0.98 0.97 0.98 0.98
*MedAvante study data on file and made available to sponsor during study.
Ziprasadone Monotherapy Study: Papakostas et al, J Clin Psychiatry. 2012 Dec; 73(12): 1541-7; TRD-1 and TRD-2: Papakostas et al, Am J Psychiatry. 2012 Dec 1; 169(12): 1267-74; ADAPT-A: Fava et al, Psychother Psychosom. 2012; 81(2): 87-97; Alkermes ALK 5461: Poster, ISCTM, 2013 Oct Note: ALK response rates relate to MADRS (secondary) outcomes.
19%
81%Zip Mono TRD-1 ADAPT-A TRD-2 ALK Average
12
68
54 52
81
53
100
80
60
40
20
0
% Reduction
Randomize
PlaceboActive
Treatment (Dose X)
Active Treatment
(Dose X)
Active Treatment
(Dose X)Placebo
ResponderResponderNon
ResponderNon
Responder
PlaceboActive
Treatment (Dose X)
Randomize
Randomize
TreatmentPhase 1
Results
TreatmentPhase 2
Rater Cohort Characteristics 1.00 80% 100
Experienced, calibrated 0.933 78% 108
0.80 71% 125
Inexperienced, calibrated 0.773 70% 130 0.60 59% 167
Experienced, calibrated 0.553 55% 181
Reliability (ICC) Study Power1 Sample Size per Arm2
Q1 Q2 Q3 Q4
HAM-A (N=100) (Study 1)* 0.90 0.96 0.95 0.97
HAM-A (N=68) (Study 2)* 0.98 0.97 0.97 0.96
PANSS (N=131) (Study 3)* 0.90 0.90 0.96 0.88
PANSS (N=67) (Study 4)* 0.98 0.97 0.98 0.98
*MedAvante study data on file and made available to sponsor during study.
Ziprasadone Monotherapy Study: Papakostas et al, J Clin Psychiatry. 2012 Dec; 73(12): 1541-7; TRD-1 and TRD-2: Papakostas et al, Am J Psychiatry. 2012 Dec 1; 169(12): 1267-74; ADAPT-A: Fava et al, Psychother Psychosom. 2012; 81(2): 87-97; Alkermes ALK 5461: Poster, ISCTM, 2013 Oct Note: ALK response rates relate to MADRS (secondary) outcomes.
19%
81%Zip Mono TRD-1 ADAPT-A TRD-2 ALK Average
12
68
54 52
81
53
100
80
60
40
20
0
% Reduction
Randomize
PlaceboActive
Treatment (Dose X)
Active Treatment
(Dose X)
Active Treatment
(Dose X)Placebo
ResponderResponderNon
ResponderNon
Responder
PlaceboActive
Treatment (Dose X)
Randomize
Randomize
TreatmentPhase 1
Results
TreatmentPhase 2
Rater Cohort Characteristics 1.00 80% 100
Experienced, calibrated 0.933 78% 108
0.80 71% 125
Inexperienced, calibrated 0.773 70% 130 0.60 59% 167
Experienced, calibrated 0.553 55% 181
Reliability (ICC) Study Power1 Sample Size per Arm2
Q1 Q2 Q3 Q4
HAM-A (N=100) (Study 1)* 0.90 0.96 0.95 0.97
HAM-A (N=68) (Study 2)* 0.98 0.97 0.97 0.96
PANSS (N=131) (Study 3)* 0.90 0.90 0.96 0.88
PANSS (N=67) (Study 4)* 0.98 0.97 0.98 0.98
*MedAvante study data on file and made available to sponsor during study.
Number of Central Raters Estimated number of site raters
Num
ber o
f Rat
ers
180
160
140
120
100
80
60
40
20
0
STUDY A
STUDY B
STUDY C
STUDY D
STUDY E
STUDY F
STUDY G
STUDY I
STUDY J
STUDY K
STUDY L
STUDY M
STUDY H
STUDY N
STUDY O
STUDY P
STUDY Q
STUDY R
STUDY S
STUDY T
STUDY U
STUDY V
STUDY W
STUDY X
600
400
200
0
Freq
uenc
y
Freq
uenc
y
Freq
uenc
y
Freq
uenc
y
BPRS Total Score (n=382)PANSS Total Score (n=563)HAM-A Total Score (n=462)MADRS Total Score (n=4140)
80
60
40
20
0
100
80
60
40
20
0
50
40
30
20
10
00 4 8 12 16 20 24 28 32 36 40 44 48 6 10 14 18 22 26 30 34 38 42 50 60 70 80 90 100 110 120 130 140 24 28 32 36 40 44 48 52 56 60 64 68
Number of Central Raters Estimated number of site raters
Num
ber o
f Rat
ers
180
160
140
120
100
80
60
40
20
0
STUDY A
STUDY B
STUDY C
STUDY D
STUDY E
STUDY F
STUDY G
STUDY I
STUDY J
STUDY K
STUDY L
STUDY M
STUDY H
STUDY N
STUDY O
STUDY P
STUDY Q
STUDY R
STUDY S
STUDY T
STUDY U
STUDY V
STUDY W
STUDY X
600
400
200
0
Freq
uenc
y
Freq
uenc
y
Freq
uenc
y
Freq
uenc
y
BPRS Total Score (n=382)PANSS Total Score (n=563)HAM-A Total Score (n=462)MADRS Total Score (n=4140)
80
60
40
20
0
100
80
60
40
20
0
50
40
30
20
10
00 4 8 12 16 20 24 28 32 36 40 44 48 6 10 14 18 22 26 30 34 38 42 50 60 70 80 90 100 110 120 130 140 24 28 32 36 40 44 48 52 56 60 64 68
Ziprasadone Monotherapy Study: Papakostas et al, J Clin Psychiatry. 2012 Dec; 73(12): 1541-7; TRD-1 and TRD-2: Papakostas et al, Am J Psychiatry. 2012 Dec 1; 169(12): 1267-74; ADAPT-A: Fava et al, Psychother Psychosom. 2012; 81(2): 87-97; Alkermes ALK 5461: Poster, ISCTM, 2013 Oct Note: ALK response rates relate to MADRS (secondary) outcomes.
19%
81%Zip Mono TRD-1 ADAPT-A TRD-2 ALK Average
12
68
54 52
81
53
100
80
60
40
20
0
% Reduction
Randomize
PlaceboActive
Treatment (Dose X)
Active Treatment
(Dose X)
Active Treatment
(Dose X)Placebo
ResponderResponderNon
ResponderNon
Responder
PlaceboActive
Treatment (Dose X)
Randomize
Randomize
TreatmentPhase 1
Results
TreatmentPhase 2
Rater Cohort Characteristics 1.00 80% 100
Experienced, calibrated 0.933 78% 108
0.80 71% 125
Inexperienced, calibrated 0.773 70% 130 0.60 59% 167
Experienced, calibrated 0.553 55% 181
Reliability (ICC) Study Power1 Sample Size per Arm2
Q1 Q2 Q3 Q4
HAM-A (N=100) (Study 1)* 0.90 0.96 0.95 0.97
HAM-A (N=68) (Study 2)* 0.98 0.97 0.97 0.96
PANSS (N=131) (Study 3)* 0.90 0.90 0.96 0.88
PANSS (N=67) (Study 4)* 0.98 0.97 0.98 0.98
*MedAvante study data on file and made available to sponsor during study.
Fava,M1,2, Williams JBW3,4, Freeman, M1,2 , Detke MJ3,5,6
1Massachusetts General Hospital Dept. of Psychiatry, 2Clinical Trials Network and Institute 3MedAvante, Inc., 4Columbia University Depts. of Psychiatry and Neurology, 5Detke Biopharma Consulting LLC, 6Indiana University School of Medicine
Are Different Methods to Reduce Placebo Response in CNS Trials Mutually Exclusive or Have Additive Effects?
©2014MedAvanteInc.
RESEARCH INSTITUTE
INTRODUCTION
Overthepasttwodecades,numerousmethodologieshavebeendevelopedwiththespecificgoalofreducingtheplaceboeffectinCNStrials.Thenumberoffailedtrialsinpsychiatryhasincreasedsubstantiallyovertime.Thismaybeduetobaselinescoreinflationandtheinclusionofinappropriatesubjects,variabilityinbaselineandpost-baselineclinicalratings,andexpectationorrelationshipbiasesassociatedwiththeperceptionsofsubjects,cliniciansorboththatcanaffectplaceboresponsewhenclinicalratersfunctioninmultiplerolesatstudysites.Thispresentationwilldiscusshowacombinationofthreestrategies,CentralRatings,useoftheSAFERInterview,anduseofSequentialParallelComparisonDesign(SPCD),mayoffera“triplesafety”nettoensuremaximumreductionoftheriskofafailedtrial.
THE THREE STRATEGIES
COMBINING THE THREE STRATEGIES
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Eachoftheseriskreductionstrategiescanimproveresults,butcombiningallthreemethodstoworkinsequenceinatrialcanincreasestudypowerandmosteffectivelyminimizethemethodologyfactorsthatcancauseatrialtofailtodetectasignal.Analyseshaveshownthatthecostofreducingtheriskoftrialfailureincreasestheexpectednetpresentvalueoftheoverallprograminvestment,manytimesover5.• Calibratedindependentcentralratersavoidthebiasesandreducetheratingvariabilitythatadverselyaffectssubjectselection,accuratebaselineandpost-baselineratings.
• TheSAFERInterview,administeredbyindependentcentralraters,canhelpensureselectionofappropriatesubjects.
• SPCDmethodology,inconjunctionwiththeaccuracyandprecisionachievablewithremotecentralratings,candecreaseplaceboresponseandallowforasmallersamplesize.
Incombination,thesethreeuniquebutcomplementarystrategiesoffera“triplesafetynet”thatmaydramaticallyreducetheriskofafailedtrialandofferthebestchanceforatrialtosucceed.
References1Mueller&Szegedi.(2002).EffectsofInterraterReliabilityofPsychopathologicAssessmentonPowerandSampleSizeCalculationsinClinicalTrials.JournalofClinicalPsychopharmacology.22(3),318-325.Calculatedwheren=100subjectsperarmandeffectsize=.402PerkinsDOetal.(2000).Penny-wiseandpoundfoolish:Theimpactofmeasurementerroronsamplesizerequirementsinclinicaltrials.BiologicalPsychiatry.47,762-766.Calculatedwheren=100subjectsperarm3KobakKAetal.(2009).SourcesofUnreliabilityinDepressionRatings..JournalofClinicalPsychopharmacology.29(1),82-85.4TargumSD,PollackMH,FavaM.(2008).Redefiningaffectivedisorders:Relevancefordrugdevelopment.CNSNeuroscience&Therapeutics.14,2-9;doi:10.1111/j.1527-3458.2008.00038.x.5GreenblattWetal.(2012).TheValueofRiskReductioninCNSDrugDevelopment:UseofExpectedNetPresentValue(eNPV)asaModel.PresentedatAmericanCollegeofNeuropsychopharmacology51stAnnualMeeting,HollywoodFL.
Remote Independent Central Ratings• Theuseofwell-trainedandblinded,calibratedexpertcentralratersminimizesperceptionbiasesandreducesvariability,whichenhancesseparationbetweenplaceboandactivetreatment.
•RemoteindependentcentralratersscreeningsubjectsviaevaluationofsymptomseverityandtheSAFERInterviewhelpensuretheunbiasedselectionofappropriatesubjectswhileavoidingbaselinescoreinflation.(Figure 1)
Figure 1.Sample of Baseline Score Distributions in Completed Studies MDD GAD SCHIZOPHRENIA PSYCHOSIS
•Centralratingsensureaccuratepost-baselineratingsandincreasestudypowerviahighICCSfurtherenhancingtheimpactoftheSPCDidentificationofplacebonon-respondersforrandomizationinStage2.
•Centralratersreducevariabilitybylimitingthenumberofratersneededforanyonetrial.(Figure 2)
•Higherinterraterreliabilitymeanshigherstudy
power.Experiencedandcalibratedratersensurethehighestlevelofreliability.(Figure 3)
•Ongoingcalibrationofcentralraterspreventsraterdriftthroughoutthecourseofthetrial.(Figure 4)
Figure 3.Impact of Experience vs. Calibration on Interrater Reliability
Figure 4.Impact of Continuous Calibration on Interrater Reliability
Figure 2.Centralized vs. Decentralized Study: Number of Raters
Figure 5.SAFER Interview Pass/Fail Rate
Sequential Parallel Comparison Design (SPCD)• GoalsoftheSequentialParallelComparisonDesign(SPCD)aretoreducetheimpactofhighplaceboresponseanddecreasestudysamplesize.
• TheSPCDmodel(Figure6)incorporatestworelativelyshortphasesoftreatmentofequalduration:
Phase 1:allsubjectsrandomizedtoplacebooractivetreatment;moresubjectsthanusualassignedtoplaceboarmtoenrichphase2;
Phase 2:subjectsonactivetreatmentandplacebonon-respondersinPhase1arerandomizedtoplacebooractivetreatment.
Figure 6.Sequential Parallel Comparison Design
• InPhase2theblindismaintainedforallsubjectsasthoseonactivedruginPhase1remainonactivetreatmentandplacebonon-respondersarerandomizedtoplacebooractivetreatment.
• StandardanalysesofSPCDstudiescombinedatainPhase1fromallsubjectsandinPhase2onlyfromplacebonon-respondersduringPhase1.
• Poolingthedatawithapre-specifiedweightedaveragesignificantlyreducestheoverallplaceboresponse,asitistheaverageoftheplaceboresponseinPhase1(standardresponse)andinPhase2(lowerresponseamongsubjectswhofailedtorespondtoplaceboprospectively).
• InfivecompletedSPCDtrials,thismethodhasreducedtheoverallplaceboresponserateonaverageby53percentcomparedtothePhase1placeboresponse.(Figure 7)
Figure 7.Percent Reduction in Placebo Response Rates in Stage 2 SPCD Trials (Chronological Order)
Passes
Fails
ZiprasadoneMonotherapyStudy:Papakostasetal,JClinPsychiatry.2012Dec;73(12):1541-7;TRD-1andTRD-2:Papakostasetal,AmJPsychiatry.2012Dec1;169(12):1267-74;ADAPT-A:Favaetal,PsychotherPsychosom.2012;81(2):87-97;AlkermesALK5461:Poster,ISCTM,2013OctNote:ALKresponseratesrelatetoMADRS(secondary)outcomes.
Ziprasadone Monotherapy Study: Papakostas et al, J Clin Psychiatry. 2012 Dec; 73(12): 1541-7; TRD-1 and TRD-2: Papakostas et al, Am J Psychiatry. 2012 Dec 1; 169(12): 1267-74; ADAPT-A: Fava et al, Psychother Psychosom. 2012; 81(2): 87-97; Alkermes ALK 5461: Poster, ISCTM, 2013 Oct Note: ALK response rates relate to MADRS (secondary) outcomes.
19%
81%Zip Mono TRD-1 ADAPT-A TRD-2 ALK Average
12
68
54 52
81
53
100
80
60
40
20
0
% Reduction
Randomize
PlaceboActive
Treatment (Dose X)
Active Treatment
(Dose X)
Active Treatment
(Dose X)Placebo
ResponderResponderNon
ResponderNon
Responder
PlaceboActive
Treatment (Dose X)
Randomize
Randomize
TreatmentPhase 1
Results
TreatmentPhase 2
Rater Cohort Characteristics 1.00 80% 100
Experienced, calibrated 0.933 78% 108
0.80 71% 125
Inexperienced, calibrated 0.773 70% 130 0.60 59% 167
Experienced, calibrated 0.553 55% 181
Reliability (ICC) Study Power1 Sample Size per Arm2
Q1 Q2 Q3 Q4
HAM-A (N=100) (Study 1)* 0.90 0.96 0.95 0.97
HAM-A (N=68) (Study 2)* 0.98 0.97 0.97 0.96
PANSS (N=131) (Study 3)* 0.90 0.90 0.96 0.88
PANSS (N=67) (Study 4)* 0.98 0.97 0.98 0.98
*MedAvante study data on file and made available to sponsor during study.