Single-Arm Trials Start to Strong-Arm Their Way into European Regulation

The old prejudices in favor of randomized clinical trials (RCTs) remain firmly in place in many quarters—not least among national regulators and many healthcare payers—but growing pressure for flexibility from within much of the clinical trial community, driven largely by advances in disease understanding, is starting to shift the needle. Nothing could make the point more strongly than the European Medicines Agency's (EMA) decision in late April to open a public consultation into single-arm clinical trials.

It has released a reflection paper¹ that discusses the pros and cons and what it regards as do's and don'ts when they are to be offered as pivotal evidence in support of a marketing authorization application in Europe—something of a first in the international clinical trials sphere. Its avowed aim is to stimulate discussion and improve their design and conduct.

As EMA recognizes, where target populations are very small, such as in rare cancers, some submissions have relied on single-arm trials (SAT) as pivotal evidence. This has already provoked controversy, with many voices raising concerns over premature authorizations on the basis of inadequate evidence. Even the announcement of the consultation prompted a spokesperson for the major European mutual insurer to sound a note of caution: "It is very, very important to not let the quality of data deteriorate further," said AIM's Thomas Kanga-Tona. "We need strong data for strong health technology assessment."

EMA also recognizes at the outset of its reflections that it is itself wary of taking a step too far away from the status quo. "It is the responsibility of the applicant to adequately justify to regulators why a SAT, which deviates from the standard approach of providing pivotal evidence on efficacy through RCTs, can provide clear pivotal evidence of efficacy. Obtaining scientific advice is, therefore, strongly recommended to discuss whether pivotal evidence from SATs may be considered acceptable for seeking marketing authorization for a specific development program."

SATs are "non satis," suggests the EMA approach firmly. If their results are to be used as pivotal evidence for approval, their adequacy must be "systematically addressed in terms of their characteristics, limitations, and remaining uncertainties." This is necessary to establish whether proof of efficacy can be based on SATs at all, and, if so, how to characterize the effect of the treatment and understand remaining uncertainties to best inform benefit-risk assessment.

So, the paper sets out what it regards as general considerations for single-arm trial designs, covering choice of endpoints, target, and trial populations and the role of external

information, statistical principles, and sources of bias. It offers a lengthy list of measures aiming to reduce or mitigate potential bias, an alphabet of dangers from errors in ascertainment, assessment and attrition, calendar time, and immortal time lack of pre-planning through to retrospective selection and variability in disease history.

The reflections have resonance for a rather wider range of trial designs too—for instance, trials that contain more than one arm but do not randomize to a control for a formal comparison. This includes non-randomized trials, as well as trials in which only experimental arms are randomized, but without formal comparisons between the arms—such as a platform trial of several treatment arms that are not formally compared. These can be viewed, says the EMA, as "a series of SATs."

Following the public consultation, comments from stakeholders will be analyzed and considered in the final document that is planned to be published in 2024. And everyone has a chance to comment—as long as they do so before the end of September. Something to think about on the beach?

Reference

1. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing_en.pdf

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium