EU pharmaceutical groups suggest fixes to ICH E20 guideline

Pharmaceutical companies and EU industry groups pushed back against the expectation for sponsors to justify their choice to use adaptive clinical trial designs in the International Council on Harmonisation’s E20 guidance on adaptive clinical trials in comments submitted to the European Medicines Agency (EMA).

The commenters argued that the effort needed to justify adaptive designs appears greater than that required for non-adaptive designs. Nevertheless, the pharmaceutical industry overall praised the guideline as a necessary first step toward harmonizing the requirements for adaptive clinical trials on a global scale.

The comments were submitted in response to EMA’s request for feedback on the E20 guideline, which was published by the International Council for Harmonisation (ICH) in June 2025. This guideline aims to harmonize the principles for the design, analysis, and reporting of adaptive clinical trials in the development of new drugs. (RELATED: ICH releases E20 guideline to assist sponsors in designing adaptive clinical trials, Regulatory Focus 27 June 2025)

EMA received 22 comments on the guidance from international clinical trial groups, European pharmaceutical groups, companies, and physicians.

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 interim analysis of accumulating data from participants in the trial. The term prospectively planned means that the potential trial adaptations are pre-specified in the clinical trial protocol prior to initiation of the trial.

Groups praise the guideline overall

Numerous organizations, including the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Association of Clinical Research Organizations (ACRO), expressed support for the guideline.

EFPIA said the draft guideline “addresses a substantial breadth of considerations in the evaluation of a confirmatory clinical trial. We applaud the tremendous effort towards clarifying the considerations surrounding the design and implementation of adaptive clinical trials in the confirmatory setting. While the draft Guideline addresses these considerations in the context of the design, implementation, and analysis of adaptive clinical trials, many of these considerations apply similarly to traditional frequentist, non-adaptive confirmatory trials as well.”

ACRO said the group “supports the goal of establishing harmonized principles that encourage innovation while maintaining scientific rigor and trial integrity. Industry has long adopted adaptive designs but the absence of an international guideline setting the regulatory framework and main acceptance criteria of adaptive designs has been a hurdle for innovative clinical research. This E20 guideline provides clarity and will enable discussions about planning for adaptive designs. We appreciate that the guideline provides assurance that planning, intentionality, and mid-stream mitigating effort is relevant, as this will help to embed novel design considerations throughout the stages of clinical development, trial conduct, and the product lifecycle.”

Groups say sponsors should not have to justify adaptive designs

Both EFPIA and the European Federation of Statisticians in the Pharmaceutical Industry Special Interest Group (EFSPI-SIG) stated that the guidelines should take a more flexible approach instead of mandating that sponsors to justify their choice of using adaptive designs.

The guidance said that “the decision to use or not use a specific adaptive design in a clinical trial will depend on many factors…There can be a tension between the confirmatory nature of a late-stage clinical trial and the proposal to adapt aspects of the trial while it is ongoing. In planning an adaptive design, it is therefore essential to carefully justify the need to adapt the trial and assess potential implications of the type, number, and complexity of the adaptations involved. The justification should include both clinical and statistical considerations. It should weigh the advantages of the design against the extent to which the adaptations being considered add uncertainty about the trial’s ability to produce reliable and interpretable results.”

EFPIA said this expectation is overly stringent and not practical. “The ICH expert working group should have a general understanding that there is no complete certainty on assumptions during the planning stage – otherwise, a confirmatory trial might not be required, as everything is already known. Adaptive designs are frequently implemented to address uncertainties and certainly not to cut corners.”

The group further added that “sponsors should not be constantly challenged to justify adaptive designs.”

EFSPI-SIG concurred with EFPIA. “According to the overall impression, the effort to justify adaptive designs seems much higher than the effort for justifying a non-adaptive design. (As an example, documentation of simulations around designs with a futility analysis or standard GSD may be perceived as increasing the bar.)”

ACRO recommends harmonizing guidelines with M11

ACRO recommended that the E20 guideline be harmonized with the ICH M11 guidelines on the Clinical Electronic Structured harmonized Protocol (CeSHarP).

“The documentation requirements outlined in E20 are thorough but risk creating redundancy across regions. We recommend harmonizing expectations with ICH M11 and regional data submission templates, ensuring that required documentation reflects structured, digital formats rather than duplicative narrative reports – similar to the restructuring in ICH’s M4Q(R2). This would strengthen transparency, support automation, and align with ICH’s broader modernization strategy,” ARCO wrote.

ACRO also suggested that the guideline be modified to address emerging analytic frameworks such as machine learning-assisted modeling and real-time data integration. The group notes that “the guideline should consider how future adaptive methodologies can be evaluated under the same principles of pre-specification and statistical rigor, drawing lessons from ICH M15 Guideline on general principles for model-informed drug development.”

ACRO also recommended that the guidelines take into account the needs of small and medium-sized companies.

The group wrote that “E20 effectively outlines the conceptual advantages of adaptive design but underestimates the practical barriers sponsors face, particularly small or mid-sized organizations, when comparing multiple candidate designs…..We encourage the inclusion of language emphasizing proportionality, ensuring that comparative evaluation should be commensurate with the adaptation’s scale and impact, focusing on rationale for the chosen design rather than exhaustive alternatives. We suggest addition of the following text: “Comparative evaluation should be commensurate with the adaptation’s scale and impact, focusing on the rationale for the chosen design rather than benchmarking against alternatives.”

EUCROF wants more examples

The European CRO Federation (EUCROF) suggested the guideline include additional examples to provide a more practical approach to the guidelines.

The group said that “appreciates the opportunity to provide comments for the Guideline ICH E20 as adaptive designs will become increasingly important in the future, especially in the context of complex clinical trials. As always, more examples would be considered as beneficial, although it is recognized how difficult this is. Maybe some case studies given as examples in an Appendix would be a way to give this Guideline a more practical touch. Other than that, we feel that it is very complete and addresses very important issues.”

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EU pharmaceutical groups suggest fixes to ICH E20 guideline

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