handling of missing data in clinical trials for non-statisticians

Handling Missing Data in

Clinical Trials for Non-

Statisticians

WEBINAR | JUNE 20, 2017 | 12:00PM CENTRAL

DALE W. USNER, Ph.D. | PRESIDENT | SDC

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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

Q&A

info@sdcclinical.comwww.sdcclinical.com

Thank You