The impact of missing data and how it is handled on the rate of false-positive results in drug development

In drug development, a common choice for the primary analysis is to assess mean changes via analysis of (co)variance with missing data imputed by carrying the last or baseline observations forward (LOCF, BOCF). These approaches assume that data are missing completely at random (MCAR). Multiple imput...

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Bibliographic Details
Published in:Pharmaceutical statistics : the journal of the pharmaceutical industry 2008-07, Vol.7 (3), p.215-225
Main Authors: Barnes, Sunni A., Mallinckrodt, Craig H., Lindborg, Stacy R., Carter, M. Kallin
Format: Article
Language:English
Subjects:
BOCF
Data Collection - methods
Data Collection - statistics & numerical data
False Positive Reactions
LOCF
missing data
MMRM
MNAR
multiple imputation
Research Design - statistics & numerical data
Technology, Pharmaceutical - methods
Technology, Pharmaceutical - statistics & numerical data
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Summary:In drug development, a common choice for the primary analysis is to assess mean changes via analysis of (co)variance with missing data imputed by carrying the last or baseline observations forward (LOCF, BOCF). These approaches assume that data are missing completely at random (MCAR). Multiple imputation (MI) and likelihood‐based repeated measures (MMRM) are less restrictive as they assume data are missing at random (MAR). Nevertheless, LOCF and BOCF remain popular, perhaps because it is thought that the bias in these methods lead to protection against falsely concluding that a drug is more effective than the control. We conducted a simulation study that compared the rate of false positive results or regulatory risk error (RRE) from BOCF, LOCF, MI, and MMRM in 32 scenarios that were generated from a 25 full factorial arrangement with data missing due to a missing not at random (MNAR) mechanism. Both BOCF and LOCF inflated RRE were compared to MI and MMRM. In 12 of the 32 scenarios, BOCF yielded inflated RRE compared with eight scenarios for LOCF, three scenarios for MI and four scenarios for MMRM. In no situation did BOCF or LOCF provide adequate control of RRE when MI and MMRM did not. Both MI and MMRM are better choices than either BOCF or LOCF for the primary analysis. Copyright © 2007 John Wiley & Sons, Ltd.
ISSN:1539-1604
1539-1612
DOI:10.1002/pst.310