acleon strategies to reduce attrition nas 090909

7/31/2019 ACLeon Strategies to Reduce Attrition NAS 090909

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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 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)


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



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3483

N

16

# trials

48.3%59.0%Schizophrenia

ActivePLA

Antipsychotic RCTs submitted to FDA

(Khan, 2007, Neuropsychopharm)


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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Engage, thank, and reward participants



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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

acleon strategies to reduce attrition nas 090909

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