handling of missing data in clinical trials for non-statisticians
TRANSCRIPT
Handling Missing Data in
Clinical Trials for Non-
Statisticians
WEBINAR | JUNE 20, 2017 | 12:00PM CENTRAL
DALE W. USNER, Ph.D. | PRESIDENT | SDC
Webinar Housekeeping
Live presentation and webinar
Use speakers or call in
Audience is on mute
Submit questions via chat portal
Dale W. Usner, Ph.D.
20 years in industry
50+ FDA and international regulatory body interactions
Frequent study design support
Therapeutic expertise in
Ophthalmology
Oncology/Immunology
Gastrointestinal
Anti-viral/Anti-infective
Neurology
and Other
Agenda
Missing Data Common Analysis Methods
Motivating Example
Impact of Different Methods in Pictures
Statistical Properties
Q&A
Missing Data
The prevention, impact, and treatment missing data in randomized trials has
been discussed frequently in the literature
Little RJ, D’Agostino R, Cohen ML, Dickersin K, et.al. The Prevention and
Treatment of Missing Data in Clinical Trials. The New England Journal of
Medicine. 2012; 367:1355-1360.
Guideline on Missing Data in Confirmatory Clinical Trials: EMA. 2011
National Research Council. The prevention and treatment of missing data in
clinical trials. National Academies Press. 2010.
Permutt T and Li F. Trimmed Means for Symptom Trials with Dropouts.
Pharmaceutical Statistics. 2017; 16:20-28.
Missing Data Methods: Continuous Data
Observed Data Only (ODO)
Last Observation Carried Forward (LOCF)
Baseline Observation Carried Forward (BOCF)
Multiple Imputation Methods
Many Different Modeling Strategies Available
Missing Completely at Random
Missing at Random
Missing Not at Random
Trimmed Means
Missing Data Methods: Dichotomous Data
Observed Data Only (ODO)
Last Observation Carried Forward (LOCF)
Missing Imputed as Failures / Baseline Observation Carried Forward
Multiple Imputation Methods
Impact of Chosen Technique
Type of Hypothesis: Non-Inferiority or Superiority
Scenarios of Missing Data:
Correlated with Higher Efficacy
Correlated with Lack of Efficacy
Random
Operating Characteristics
Alpha (Type I Error)
Power (1-Type II Error)
Motivating Example: Weight Loss
Two Dosing Regimens (QD and BID) of Test Product vs Control
Primary Endpoint at 3 Months
Correlation Between 6 Weeks and 3 Month Visit: 60%
Correlation Between Baseline and 6W & 3M: 30%
Discontinuation Rate BID (24%) > QD (12%) > Control (3%)
BID 2.2lbs better than QD or Control (211.0 vs 213.2 vs 213.2)
Change from baselines of approx. 11.1, 8.9, 8.9 lbs respectively
Standard Deviation: 6lbs
NI: 3.3lbs; 150 subjects per arm
QD versus Control
Non-Inferiority
QD Mean = 213.2
Ctrl Mean = 213.2
Missing Correlated with Efficacy
One Example Simulation Presented
QD vs Ctrl Data: Missing Data Corr with
Efficacy – Full Data
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 212.4
Completed Discontinued
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.8
Completed Discontinued
QD vs Ctrl Data: Missing Data Corr with
Efficacy – Observed Data Only
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 213.2
Completed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.2
Completed
QD vs Ctrl Data: Missing Data Corr with
Efficacy – LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 212.8
Completed LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.1
Completed LOCF
QD vs Ctrl Data: Missing Data Corr with
Efficacy – BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 214.2
Completed BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.6
Completed BOCF
QD vs Ctrl Data: Missing Data Corr with
Efficacy – Trimmed Means
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD
Completed Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl
Completed Trimmed
QD vs Ctrl Data: Missing Data Corr with
Efficacy – Trimmed Means
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 209.3
Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 208.6
Trimmed
BID vs Control
Non-Inferiority
BID Mean = 211.0
Ctrl Mean = 213.2
Missing Correlated with Efficacy
One Example Simulation Presented
BID vs Ctrl Data: Missing Data Corr with
Efficacy – Full Data
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 211.3
Completed Discontinued
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.8
Completed Discontinued
BID vs Ctrl Data: Missing Data Corr with
Efficacy – ODO
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 212.3
Completed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.2
Completed
BID vs Ctrl Data: Missing Data Corr with
Efficacy – LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 213.8
Completed LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.1
Completed LOCF
BID vs Ctrl Data: Missing Data Corr with
Efficacy – BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 214.9
Completed BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.6
Completed BOCF
BID vs Ctrl Data: Missing Data Corr with
Efficacy – Trimmed Means
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID
Completed Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl
Completed Trimmed
BID vs Ctrl Data: Missing Data Corr with
Efficacy – Trimmed Means
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 209.5
Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 208.6
Trimmed
QD versus Control
Non-Inferiority
QD Mean = 213.2
Ctrl Mean = 213.2
Missing Correlated with Lack of Efficacy
One Example Simulation Presented
QD vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – Full Data
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 212.4
Completed Discontinued
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.8
Completed Discontinued
QD vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – ODO
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 211.7
Completed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.7
Completed
QD vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 212.5
Completed LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.0
Completed LOCF
QD vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 213.1
Completed BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.2
Completed BOCF
QD vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
QD: Mean = 207.8
Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 207.8
Trimmed
BID versus Control
Non-Inferiority
BID Mean = 211.0
Ctrl Mean = 213.2
Missing Correlated with Lack of Efficacy
One Example Simulation Presented
BID vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – Full Data
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 211.3
Completed Discontinued
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.8
Completed Discontinued
BID vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – ODO
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 210.3
Completed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 212.7
Completed
BID vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 213.0
Completed LOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.0
Completed LOCF
BID vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 213.9
Completed BOCF
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 213.2
Completed BOCF
BID vs Ctrl Data: Missing Data Corr with
Lack of Efficacy – Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
BID: Mean = 207.0
Trimmed
0
10
20
30
40
193.9 197.2 200.5 203.8 207.1 210.4 213.7 217 220.3 223.6 226.9 230.2 233.5
Ctrl: Mean = 207.8
Trimmed
Model Properties
Alpha: Non-Inferiority – QD vs Control
0.0000
0.0100
0.0200
0.0300
0.0400
0.0500
0.0600
0.0700
0.0800
0.0900
0.1000
Full ODO LOCF BOCF Trimmed
1-Sided Alpha (Non-Inf): QD v Ctrl
Random Missing Missing Corr Eff Missing Corr LOE
Power: Non-Inferiority - Efficacy
0.75
0.8
0.85
0.9
0.95
1
Full ODO LOCF BOCF Trimmed
Power (Non-Inf): Missing Corr with Efficacy
QD v Ctrl BID v Ctrl
Power: Non-Inferiority – LOE
0.955
0.96
0.965
0.97
0.975
0.98
0.985
0.99
0.995
1
Full ODO LOCF BOCF Trimmed
Power (Non-Inf): Missing Corr with LOE
QD v Ctrl BID v Ctrl
Power: Non-Inferiority - Random
0.75
0.8
0.85
0.9
0.95
1
Full ODO LOCF BOCF Trimmed
Power (Non-Inf): Random Missing
QD v Ctrl BID v Ctrl
Alpha: Superiority - QD vs Control
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
Full ODO LOCF BOCF Trimmed
1-Sided Alpha (Superiority): QD v Ctrl
Random Missing Missing Corr Eff Missing Corr LOE
Power: Superiority - Efficacy
0.0000
0.1000
0.2000
0.3000
0.4000
0.5000
0.6000
0.7000
0.8000
0.9000
1.0000
Full ODO LOCF BOCF Trimmed
Power (Superiority): Missing Corr with Efficacy
QD v Ctrl BID v Ctrl
Power: Superiority – LOE
0.0000
0.1000
0.2000
0.3000
0.4000
0.5000
0.6000
0.7000
0.8000
0.9000
1.0000
Full ODO LOCF BOCF Trimmed
Power (Superiority): Missing Corr with LOE
QD v Ctrl BID v Ctrl
Power: Superiority - Random
0.0000
0.1000
0.2000
0.3000
0.4000
0.5000
0.6000
0.7000
0.8000
0.9000
1.0000
Full ODO LOCF BOCF Trimmed
Power (Superiority): Random Missing
QD v Ctrl BID v Ctrl
