ICH releases E20 guideline to assist sponsors in designing adaptive clinical trials

The International Council for Harmonisation (ICH) has released its highly anticipated draft guideline that harmonizes principles for the design, analysis, and reporting of adaptive clinical trials in new drug development.

The guideline defines an adaptive design as a clinical trial design that allows for prospectively planned modifications to one or more aspects of the trial based on accumulating data from participants in the trial. ICH first proposed the guideline in a November 2019 concept paper (RELATED: ICH Updates After Singapore Assembly Meeting, Regulatory Focus 27 November 2019).

According to the concept paper, there is growing interest in using an adaptive approach to drug development. The potential benefits of adaptive designs include reducing patient exposure to unsafe or ineffective treatments, conserving trial resources, and speeding up the development process—all while ensuring that these trials can provide reliable evidence for regulatory decision-making.

The guidance addresses some of the advantages and challenges associated with the use of adaptive trials. Some advantages include flexibility and the ability to protect against inaccurate assumptions by gathering information from trial participants while allowing pre-specified modifications to design aspects during the trial. Challenges include the complexities and uncertainties associated with its use. For instance, adequately planning for and assessing a trial with an adaptive design can be more intricate and may require more time compared to a trial without such a design.

The guideline also addresses some of the key principles of using adaptive designs and the documentation needed to conduct these trials.

It states that some types of adaptive designs may require more planning than others. For instance, a design that employs unblinded sample size adaptation requires more stringent measures to ensure trial integrity compared to one that uses blinded sample size adaptation.

Documentation to support the trial should include a rationale for the proposed adaptive design, a discussion of its advantages and limitations compared to alternative designs, and a description of the proposed adaptations.

The guideline specifies that the documentation submitted after a completed trial should include details on how the adaptive design was implemented. This includes the actual number and timing of interim analyses, an evaluation of whether any aspects of trial conduct—such as baseline characteristics, enrollment rate, adherence, and retention—varied significantly before and after the interim analysis.

Sponsors should also include records of the independent data monitoring committee's (IDMC) deliberations, including records of discussions related to adaptation decisions.

Sponsors should engage with regulators during the planning phase to discuss the potential effects of adaptations on trial conduct. This includes considerations regarding the types of participants who will be enrolled and how the results will be interpreted at the conclusion of the trial.

The guidance does not cover trials with unplanned modifications, such as protocol amendments proposed by an IDMC. It also excludes routine monitoring of trials such as enrollment rate, data quality, or participant withdrawals.

The document reached Step 2b status on 25 June. Feedback is sought on adaptive design principles and approaches and their impact on industry-regulatory interactions.

ICH E20 draft guideline

ICH releases E20 guideline to assist sponsors in designing adaptive clinical trials

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