ICH E20 Draft Guideline: Understanding Adaptive Clinical Trials in Focus (2025)

The International Council for Harmonisation (ICH) has taken a major step toward modernizing clinical trial designs with the release of the ICH E20 Draft Guideline on Adaptive Clinical Trials. Published on June 25, 2025, this guideline represents a significant evolution in how confirmatory trials are planned, conducted, and interpreted globally.

It addresses the increasing demand for flexibility, efficiency, and scientific rigor in drug development while ensuring that statistical validity and regulatory confidence remain uncompromised.

What Are Adaptive Designs?

Adaptive designs are clinical trial frameworks that allow for pre-planned modifications to certain aspects of a trial based on interim analyses of accumulating data. These modifications—such as sample size adjustment, dose selection, or early stopping for efficacy or futility—must be specified in the protocol before the trial begins. This approach contrasts with non-adaptive designs, where trial parameters are fixed at the outset and cannot be changed during execution

The E20 guideline provides a comprehensive framework to guide sponsors, statisticians, and regulators in navigating these challenges.

Adaptive clinical trials offer numerous benefits. They can increase trial efficiency, reduce patient exposure to ineffective treatments, and allow faster decision-making. For example, trials can be designed to stop early for futility or efficacy, reallocate patients to more promising arms, or focus on populations with greater treatment effects.

The guideline covers various adaptive strategies commonly used in confirmatory trials. These include:

• Sample size re-estimation: Adjusting the number of patients based on observed variability or effect size at the interim.

• Adaptive dose selection: Refining or dropping dose levels based on early efficacy or safety signals.

• Treatment arm dropping or adding: Eliminating ineffective arms or introducing new ones as evidence accumulates.

• Endpoint changes: Modifying the primary endpoint if emerging data supports a different, more appropriate measure.

• Population enrichment: Focusing on a subpopulation that shows a greater response to treatment.

The guideline also considers seamless designs, such as combining phase II and phase III into one continuous trial, which can reduce development timelines while maintaining the rigor of confirmatory evidence.

The ICH E20 guideline outlines several key principles that must be observed in any adaptive confirmatory trial:

1. Pre-specification of Adaptations: All potential adaptations and the decision criteria must be documented in the trial protocol and/or statistical analysis plan. This includes specifying what data will be used, when it will be assessed, and how decisions will be made.

2. Control of Type I Error Rate: One of the most important concerns in adaptive trials is preserving the probability of falsely declaring a treatment effective (type I error). E20 emphasizes that this must be controlled using appropriate statistical techniques.

3. Trial Integrity and Blinding: Access to unblinded interim data must be limited to a predefined and independent group, such as a DMC, to avoid introducing operational or statistical bias. Maintaining the confidentiality of treatment assignments is crucial.

4. Robust Documentation: The guideline stresses the importance of clear and comprehensive documentation, both at the design and reporting stages. Regulators should be able to understand how the trial was designed, monitored, and analyzed, especially in light of the adaptations made.

Adaptive designs offer several compelling benefits in clinical research:

• Ethical Advantages: By enabling early stopping for efficacy or futility, adaptive designs can reduce exposure to ineffective or inferior treatments, thus protecting participants.

• Efficiency Gains: Adaptive trials can increase statistical power for a given sample size and potentially accelerate drug development timelines.

• Enhanced Decision-Making: Designs that allow for dose or population selection at interim analyses can improve the understanding of treatment effects and optimize benefit-risk profiles.

The draft guideline is currently in the Step 3 public consultation phase, with comments accepted until September 25, 2025. Feedback from stakeholders—industry, academia, regulators, and patient groups—will be used to finalize the document.

The ICH E20 working group expects to complete revisions and publish the final guideline (Step 4) by mid-2026, following which training and implementation support materials will be made available.

For more details and ongoing updates, refer to the ICH efficacy guidelines page and the official draft document.