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Strategies to Reduce Attrition:Strategies to Reduce Attrition:
RCTs in PsychopharmacologyRCTs in Psychopharmacology
Andrew C. Leon, Ph.D.
Weill Cornell Medical College
Funded, in part, by NIH MH060447
OutlineOutline
Attrition rates in psychopharmacology
Strategies to reduce attrition
Assessment procedures
Intention to Treat analyses in psychopharmacology
Definition of outcome
Intent to Attend
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Attrition Interferes with RCT Goals
Smaller N reduces statistical power
Limits feasibility and generalizability
Magnitude of attrition bias is function of:
Association of attrition with unobserved outcome
Attrition rate
36%38%41%6 week
--38%38%5 week
38%36%36%8 week
43%25%37%4 week
ActiveInvestigationalPLA
Antidepressant RCTs submitted to FDA
(Khan, 2000,AGP)
45 RCTs N > 19,000 subjects ; mean: 37%
Attrition Rates in PsychopharmacologyAttrition Rates in Psychopharmacology
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FDA Review of Pediatric Antidepressants and Suicidality
(Hammad, 2004)
-24%28%MDD
44%30%29%OCD
-35%37%Anxiety
ActiveInvestigationalPLA
24 RCTs N > 4400 subjects; mean: 32%
Attrition Rates in PsychopharmacologyAttrition Rates in Psychopharmacology
Attrition Rates in Psychopharmacology
8360
N
68
# trials
28.1%21.7%GeriatricDepression
ActivePLA
Geriatric RCTs of Antidepressants (Heo, 2007)
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1936
1433
1037
N
11
10
8
# trials
23.4%19.3%OCD
25.8%25.1%Panic
31.1%30.2%GAD
ActivePLA
Anxiolytic RCTs submitted to FDA
(Khan, 2007, Neuropsychopharm)
Attrition Rates in Psychopharmacology
Reviews of RCTs for Bipolar Disorder
76%5Gao et al.2009
Maintenance(12-24 months)
LA Smith et
al. BD, 2007
Kemp et al.
200836%14Acute
Depression(7-8 wks)
68%14Maintenance(12-30 months)
Attrition(Median)
# RCTs
Attrition Rates in PsychopharmacologyAttrition Rates in Psychopharmacology
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3483
N
16
# trials
48.3%59.0%Schizophrenia
ActivePLA
Antipsychotic RCTs submitted to FDA
(Khan, 2007, Neuropsychopharm)
Attrition Rates in Psychopharmacology
Design RCT to Reduce Loss of SubjectsDesign RCT to Reduce Loss of Subjects
Reduce subject burden
Restrict duration of assessments (quality vs quantity)
2, 3, 4+ hour baseline assessments are not unusual
Only include assessments linked to hypotheses
More accessible assessments
Telephone calls, IVR, Home visits
Ethical guidelines protect subjects
Guarantee each subjects right to exit
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Design RCT to Reduce Incomplete Data
Differentiate between med termination & study termination
Attempt assessments for entire course of RCT - regardless ofadherence to study meds
Adhere to Intention to Treat: Analyze as randomized
Implemented in psychiatry; strongly resisted by investigators
Truncated assessment confounds attrition and efficacyLavori, Neuropsychopharmacology, 1992
Operationalize Outcomes to Embrace AttritionOperationalize Outcomes to Embrace Attrition
Standard Outcomes in Psychopharmacology
Response status based on weekly/biweekly severity ratings HAMD, YMRS, PANSS, PDSS
Alternative Outcomes
CATIE(schizophrenia; Lieberman, NEJM, 2005)
Time until discontinuation of treatment for any cause
Bipolar Maintenance RCTs (Bowden, AGP, 2000 & 2003): Time to: relapse, meds for symptom worsening, or dropout
LiTMUS (bipolar disorder): Necessary clinical adjustments for symptom worsening or side effects
(#/month)
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Alternative Outcomes that Embrace AttritionAlternative Outcomes that Embrace Attrition
Alternative CNS Outcomes
SANAD (Epilepsy; Marson, Lancet, 2007):
Time to treatment failure -- stopping med due to inadequate seizurecontrol, intolerable side-effects, or addition of other AED
DATATOP (The Parkinson Study Group, NEJM, 1993):
Time until levodopa to treat emerging disability
Alzheimer's Disease Cooperative Study (Sano, NEJM, 1997):
Time to death; institutionalization; loss of ability to perform 2 (of 3)
basic ADLs, severe dementia.
Strategies to Enhance RetentionStrategies to Enhance Retention
Psychoeducation for families increased retention in RCT for bipolardisorder (Sherrill, Psychiatric Services, 1997)
Incentives for Participants $$ Reimbursement, newsletters, certificates, postcards
Accommodate Participants needs
Convenient time and place for assessment
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Strategies to Enhance RetentionStrategies to Enhance Retention
Engage, thank, and reward participants
Strategies to Enhance RetentionStrategies to Enhance Retention
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Strategies to Enhance RetentionStrategies to Enhance Retention
Lithium TreatmentLithium Treatment -- Moderate dose Use Study forModerate dose Use Study forBipolar Disorder: LiTMUSBipolar Disorder: LiTMUS
Ongoing RCT with 6 month course of tx: 12% attrition
Comparator condition
Randomized to optimized tx +/- lithium augmentation
Reimbursed $50/visit: costs of travel, child care, parking, time burden
Intent to Attend items administered with follow-up questions
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Predict Dropout:Intent to Attend
Baseline: How likely is it that you will complete the study?
unlikely (0) unsure (5) very likely (10)
Weekly: How likely is it that you will attend next assessment session?
unlikely (0) unsure (5) very likely (10)
Leon, Demirtas, Hedeker. Clinical Trials, 2007
Intent to Attend
Simple assessment and adds minimal burden.
Included in ongoing RCTs
schizophrenia, depression, ptsd, bipolar disorder, substance abuse & panic
Developed to provide a covariate that predicts attrition
* Identify those at risk of attrition.
Accommodate Ss needs with blindedfollow-up questions.
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Intent to Attend:Blinded Follow-up Question
If response is less than unsure(
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Intent to Attend
Incorporate in sensitivity analyses
Value ofIntent to Attendwill depend on it association with
Attrition, Outcome, and Group.
Strength of association will likely vary across indications
This item could change non-ignorable attrition to ignorable
Psychiatry Drug Division of FDAPsychiatry Drug Division of FDA
Required LOCF until about 5 years ago.
Mixed-effects models are now acceptable as primary, but LOCFmust be used in sensitivity analyses
Do not exclude Ss with some missing data
With ignorable dropout, mixed-effects models can be used for validinference.
Assume attrition explained by observed outcome or covariates
Intent to Attendcould prove to be a useful predictor of attrition.
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SummarySummary
Attrition rates are substantial in psychopharmacology
Design RCTs to minimize attrition Reduce burden of assessments
Continue to assess regardless of adherence to study meds
Operationalize outcome to incorporate dropout
Provide incentives
Collect data that predict dropout
Accommodate participants needs