Analyzing patient-reported outcome data when completion differs between arms in open-label trials: an application of principal stratification

Jessica K Roydhouse; Roee Gutman; Vishal Bhatnagar; Paul G Kluetz; Rajeshwari Sridhara; Pallavi S Mishra-Kalyani

doi:10.1002/pds.4875

Analyzing patient-reported outcome data when completion differs between arms in open-label trials: an application of principal stratification

Pharmacoepidemiol Drug Saf. 2019 Oct;28(10):1386-1394. doi: 10.1002/pds.4875. Epub 2019 Aug 13.

Authors

Jessica K Roydhouse¹, Roee Gutman², Vishal Bhatnagar³, Paul G Kluetz⁴, Rajeshwari Sridhara⁵, Pallavi S Mishra-Kalyani⁵

Affiliations

¹ Oak Ridge Institute for Science and Education Fellow, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
² Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA.
³ Division of Hematology Products, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁴ Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD, USA.
⁵ Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

PMID: 31410963
DOI: 10.1002/pds.4875

Abstract

Purpose: Cancer trials are often open-label and include patient-reported outcomes (PROs). Previous work has demonstrated that patients may complete PRO assessments less frequently in the control arm compared with the experimental arm in open-label trials. Such differential completion may affect PRO results. This paper sought to explore principal stratification methodology to address potential bias caused by the posttreatment intermediate variable of questionnaire completion.

Methods: We evaluated six randomized trials (five open-label and one double-blind) of anticancer therapies with varying levels of PRO completion submitted to the Food and Drug Administration (FDA). We applied complete case analysis (CCA), multiple imputation (MI), and principal stratification to evaluate PRO results for quality of life (QOL) and the domains of physical, role, and emotional function (PF, RF, and EF). Assignment to potential principal strata was by the expectation maximization algorithm using patient baseline characteristics.

Results: Completion rates in the experimental arm ranged from 66% to 94% and 51% to 95% in the control arm. Four trials had negligible completion differences between arms (1%-2%), and two had large differences favoring the experimental arm (15%-17%). For trials with negligible completion differences, principal stratification results were similar to CCA and MI results for all domains. Notable differences in point estimates may be observed in trials with large differences in completion rates. However, in the examined trials, the confidence intervals for the principal stratification estimates overlapped with the ones obtained using CCA.

Conclusions: The principal stratification estimand may be a useful additional analysis, especially if PRO completion differs between arms.

Keywords: cancer; causal inference; function; open-label; patient-reported outcome; pharmacoepidemiology; principal stratification; quality of life; randomized controlled trial.

MeSH terms

Aged
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / adverse effects*
Data Interpretation, Statistical
Drug-Related Side Effects and Adverse Reactions / diagnosis
Drug-Related Side Effects and Adverse Reactions / epidemiology*
Drug-Related Side Effects and Adverse Reactions / etiology
Feasibility Studies
Female
Follow-Up Studies
Head and Neck Neoplasms / complications
Head and Neck Neoplasms / drug therapy*
Head and Neck Neoplasms / mortality
Head and Neck Neoplasms / psychology
Humans
Male
Multiple Myeloma / complications
Multiple Myeloma / drug therapy*
Multiple Myeloma / mortality
Multiple Myeloma / psychology
Patient Reported Outcome Measures
Pharmacoepidemiology / methods*
Quality of Life
Randomized Controlled Trials as Topic
Risk Assessment
Severity of Illness Index
Treatment Outcome

Substances

Antineoplastic Agents