Randomized clinical trials are the primary tool for evaluating new medical interventions. Randomization provides for a fair comparison between treatment and control groups, balancing out, on average, distributions of known and unknown factors among the participants. Unfortunately, these studies often lack a substantial percentage of data. This missing data reduces the benefit provided by the randomization and introduces potential biases in the comparison of the treatment groups.

Missing data can arise for a variety of reasons, including the inability or unwillingness of participants to meet appointments for evaluation. And in some studies, some or all of data collection ceases when participants discontinue study treatment. Existing guidelines for the design and conduct of clinical trials, and the analysis of the resulting data, provide only limited advice on how to handle missing data. Thus, approaches to the analysis of data with an appreciable amount of missing values tend to be ad hoc and variable.

The Prevention and Treatment of Missing Data in Clinical Trials concludes that a more principled approach to design and analysis in the presence of missing data is both needed and possible. Such an approach needs to focus on two critical elements: (1) careful design and conduct to limit the amount and impact of missing data and (2) analysis that makes full use of information on all randomized participants and is based on careful attention to the assumptions about the nature of the missing data underlying estimates of treatment effects. In addition to the highest priority recommendations, the book offers more detailed recommendations on the conduct of clinical trials and techniques for analysis of trial data.

Contents

• THE NATIONAL ACADEMIES
• PANEL ON HANDLING MISSING DATA IN CLINICAL TRIALS
• COMMITTEE ON NATIONAL STATISTICS 2009-2010
• Acknowledgments
• Glossary
• Summary
• 1. Introduction and Background
  • RANDOMIZATION AND MISSING DATA
  • THREE KINDS OF TRIALS AS CASE STUDIES
  • CLINICAL TRIALS IN A REGULATORY SETTING
  • DOMESTIC AND INTERNATIONAL GUIDELINES ON MISSING DATA IN CLINICAL TRIALS
  • REPORT SCOPE AND STRUCTURE
• 2. Trial Designs to Reduce the Frequency of Missing Data
  • TRIAL OUTCOMES AND ESTIMANDS
  • MINIMIZING DROPOUTS IN TRIAL DESIGN
  • CONTINUING DATA COLLECTION FOR DROPOUTS
  • REFLECTING LOSS OF POWER FROM MISSING DATA
  • DESIGN ISSUES IN THE CASE STUDIES
• 3. Trial Strategies to Reduce the Frequency of Missing Data
  • REASONS FOR DROPOUTS
  • ACTIONS FOR DESIGN AND MANAGEMENT TEAMS
  • ACTIONS FOR INVESTIGATORS AND SITE PERSONNEL
  • TARGETS FOR ACCEPTABLE RATES OF MISSING DATA
• 4. Drawing Inferences from Incomplete Data
  • PRINCIPLES
  • NOTATION
  • ASSUMPTIONS ABOUT MISSING DATA AND MISSING DATA MECHANISMS
  • COMMONLY USED ANALYTIC METHODS UNDER MAR
  • ANALYTIC METHODS UNDER MNAR
  • INSTRUMENTAL VARIABLE METHODS FOR ESTIMATING TREATMENT EFFECTS AMONG COMPLIERS
  • MISSING DATA IN AUXILIARY VARIABLES
• 5. Principles and Methods of Sensitivity Analyses
  • BACKGROUND
  • FRAMEWORK
  • EXAMPLE: SINGLE OUTCOME, NO AUXILIARY DATA
  • EXAMPLE: SINGLE OUTCOME WITH AUXILIARY DATA
  • EXAMPLE: GENERAL REPEATED MEASURES SETTING
  • COMPARING PATTERN MIXTURE AND SELECTION APPROACHES
  • TIME-TO-EVENT DATA
  • DECISION MAKING
  • RECOMMENDATION
• 6. Conclusions and Recommendations
  • TRIAL OBJECTIVES
  • REDUCING DROPOUTS THROUGH TRIAL DESIGN
  • REDUCING DROPOUTS THROUGH TRIAL CONDUCT
  • TREATING MISSING DATA
  • UNDERSTANDING THE CAUSES AND DEGREE OF DROPOUTS IN CLINICAL TRIALS
• References
• Appendix A Clinical Trials: Overview and Terminology
• Appendix B Biographical Sketches of Panel Members and Staff

This study was supported by contract number HHSF223200810020I, TO #1 between the National Academy of Sciences and the U.S. Food and Drug Administration. Support for the work of the Committee on National Statistics is provided by a consortium of federal agencies through a grant from the National Science Foundation (award number SES-0453930). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.

Suggested citation:

National Research Council. (2010). The Prevention and Treatment of Missing Data in Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences and Education. Washington, DC: The National Academies Press.

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.