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Short Report
12 December 2025

Acceptability of external control-arm use in nononcology health technology assessment submissions

Authors: Kamal Kant Mangla https://orcid.org/0000-0002-3613-2748 [email protected], Spyros Kolovos https://orcid.org/0000-0003-3201-1743, Ana Lisica https://orcid.org/0000-0002-9673-402X, Max Schlueter https://orcid.org/0000-0003-1772-1421, and Nick Fabrin NielsenAuthor Info & Affiliations
Volume 15, Number 1
https://doi.org/10.57264/cer-2025-0073
PDFFormats

Abstract

Aim: This study assessed the acceptability of external control-arm (ECA) use in nononcology health technology assessment (HTA) submissions in Europe. Materials & methods: We conducted a sequential mixed method study to investigate the study objective. First, we summarized published documentation from three HTA agencies in Europe – the National Institute for Health and Care Excellence (NICE) in England, the French National Authority for Health (HAS) and the German Institute for Quality and Efficiency in Healthcare (IQWiG) – to assess the availability of guidance on ECA methodology and implementation. We then reviewed independent nononcology HTA appraisals common across England, France, Germany and Italy to understand variations in agencies’ perceptions of ECA use. Finally, we conducted six double-blinded interviews with HTA experts from England, France, Germany and Italy to validate the findings and obtain illustrative insights on drivers of acceptability. Results: While NICE and HAS provide some level of ECA-related guidance on topics such as data suitability, methods and reporting, guidance from IQWiG remains limited. Overall, ECA use is mainly restricted to oncology, particularly given that only two nononcology appraisals were common across HTA agencies. However, NICE appears more open to accepting ECA use in supplementing clinical trial data, whereas IQWiG has a strong preference for traditional controlled clinical trials. Experts indicate that ECA use is most acceptable when accompanied by valid justification, suitable data sources and a rigorous methodology to minimize the risk of bias. Situations that experts perceive as appropriate for ECA use include missing comparators (i.e., single-arm trials), limited comparator data availability, or rapidly changing standards of care. Conclusion: There is a need to focus awareness on the value of ECA use as a supplement to randomized controlled trials, and to engage with HTA agencies early in clinical development.

Plain language summary

What is this article about?

This study evaluated European health technology assessment (HTA) guidelines to understand the acceptability of external control-arm (ECA) use in nononcology HTA submissions.

What methodology is described?

The authors reviewed published guidance from three European HTA agencies (NICE in England, HAS in France and IQWiG in Germany) to understand the availability of ECA-related guidance; analyzed nononcology HTA appraisals in England, France, Germany and Italy to understand variations in agencies’ perceptions of ECA use; and conducted six double-blinded interviews with HTA experts from England, France, Germany and Italy to obtain illustrative insights on drivers of acceptability.

What were the results?

While NICE and HAS provided some guidance on ECA use, IQWiG provided limited guidance. Overall, ECAs use was mainly confined to oncology, with NICE being more open to using ECAs beyond oncology to supplement clinical trial data. IQWiG, however, preferred traditional controlled clinical trials. Experts believed that ECA use was acceptable with valid data sources and rigorous methodology to minimize bias. Appropriate situations for ECA use included the lack of head-to-head comparisons (i.e., situations where only single-arm trials or placebo-controlled trials are available), limited comparator data, ethical or feasibility concerns, or in disease states with rapidly changing standards of care.

What do the results mean?

These findings suggest that, when conducted according to established best practices, ECAs may be used to strengthen evidence packages in nononcology settings, particularly when supported by collaboration with HTA agencies to address remaining uncertainties.

Supplementary Material

File (supplementary materials.docx)

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