Related Concept Videos
Clinical Trials
There are four phases in a clinical trial. A phase one...
Clinical Trials: Overview
Types of Biopharmaceutical Studies: Controlled and Non-Controlled Approaches
Non-controlled studies, commonly employed for initial exploration, lack a control group, rendering them susceptible to biases and external influences. In contrast, controlled...
Randomized Experiments
Simple randomization
Simple...
Blinding
Bioequivalence Experimental Study Designs: Completely Randomized and Randomized Block Designs
You might also read
Related Articles
Articles linked to this work by shared authors, journal, and citation graph.
Understanding women's knowledge and perceived benefits of vaginal birth and caesarean section: A multi-country survey from the QUALI-DEC project.
Effects of physical activity and diet in pregnancy to prevent gestational diabetes: an individual participant data (IPD) meta-analysis on the differential effects of interventions with economic evaluation.
Related Experiment Video
Updated: May 13, 2026

A Clinical Trial Assessing the Safety, Efficacy, and Delivery of Olive-Oil-Based Three-Chamber Bags for Parenteral Nutrition
Published on: September 20, 2019
Intermediate outcomes in randomized clinical trials: an introduction.
Armando H Seuc1, Alexander Peregoudov, Ana Pilar Betran
1Reproductive Health Research Department, World Health Organization, Geneva 27 1211, Switzerland. seuca@who.int
The intention-to-treat approach has limitations in randomized trials with intermediate outcomes. Principal stratification offers a more appropriate method for analyzing such complex causal pathways, as demonstrated in a calcium supplementation study.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Causal Inference
Background:
- Intermediate outcomes, such as noncompliance or pregnancy, are common in clinical trials and lie on the causal pathway to final outcomes.
- Traditional intention-to-treat analysis may not adequately address these intermediate outcomes.
- Alternative methods like principal stratification are less widely known but offer more appropriate analytical frameworks.
Purpose of the Study:
- To highlight the limitations of the intention-to-treat approach for intermediate outcomes in experimental research.
- To introduce and explain the principal stratification approach for handling intermediate outcomes.
- To illustrate the application of principal stratification using a real-world clinical trial example.
Main Methods:
- Introduced principal stratification and related concepts for causal effect estimation.
- Discussed two methods for estimating causal effects.
- Applied these methods to a long-term calcium supplementation trial, considering noncompliance and pregnancy as intermediate outcomes and preeclampsia as the final outcome.
Main Results:
- Demonstrated the limitations of traditional methods when dealing with intermediate outcomes.
- Detailed the steps, assumptions, and calculations required for applying principal stratification.
- Illustrated the application within the context of the calcium trial.
Conclusions:
- The intention-to-treat approach, while sound, is not universally applicable, especially for intermediate outcomes in randomized clinical trials.
- Principal stratification provides a more suitable alternative for analyzing trials with intermediate outcomes.
- Researchers should consider principal stratification when intermediate outcomes are present in their trial designs.

