Intent-to-treat vs. Non-intent-to-treat Analyses under Treatment Non-adherence in Mental Health Randomized Trials

By Thomas R. Ten Have, PhD; Sharon-Lise T. Normand, PhD; Sue M. Marcus, PhD; C. Hendricks Brown, PhD; Philip Lavori, PhD; Naihua Duan, PhD

The intent-to-treat (ITT) principle has long been mandated by the Food and Drug Administration (FDA) as the primary design and analysis strategy for industry clinical trials. The ITT principle also has been adopted widely in government-funded randomized clinical trials. Intent-to-treat analysis aims to estimate the effect of treatment as offered or as assigned. This analysis entails comparisons of randomized groups and includes outcome data for all randomized participants regardless of their status regarding non-adherence to assigned treatment protocols and missed assessment encounters. Petkova and Teresi attributed the term “intent-to-treat” to Hill with a common refrain “once randomized, always analyzed.” FDA regulations emphasize this point in more formal language: “The intention-to-treat principle implies that the primary analysis should include all randomized subjects. Compliance with this principle would necessitate complete follow-up of all randomized subjects for study outcomes.”

ABOUT THE AUTHORS

Thomas R. Ten Have, PhD, is with the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia. Sharon-Lise T. Normand, PhD, is with the Department of Health Care Policy, Harvard Medical School; and the Department of Biostatistics, Harvard School of Public Health, Boston. Sue M. Marcus, PhD, is with the Department of Psychiatry, Mount Sinai School of Medicine, New York. C. Hendricks Brown, PhD, is with the Prevention Science and Methodology Group, Departments of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa. Philip Lavori, PhD, is Professor of Biostatistics and Chair, Department of Health Research and Policy, Stanford University School of Medicine. Naihua Duan, PhD, is Professor of Biostatistics in Psychiatry, Departments of Biostatistics and Psychiatry, Columbia University; and Director, Division of Biostatistics, N.Y. State Psychiatric Institute, New York, N.Y.

Address correspondence to: Thomas R. Ten Have, PhD, 607 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104; fax 215-573-5315; or e-mail ttenhave@upenn.edu.

Dr. Ten Have, Dr. Normand, Dr. Marcus, Dr. Brown, Dr. Lavori, and Dr. Duan have disclosed no relevant financial relationships.

EDUCATIONAL OBJECTIVES

1. Describe the advantages and limitations of intent to treat (ITT) analyses.
2. Discuss advantages and limitations of as-treated (AT) analyses.
3. Summarize valid alternatives to ITT.