By Chiara Mannelli and Giuseppe Traversa

Randomized controlled trials (RCTs) have long been regarded as the “gold standard” for testing new treatments. Yet in recent years, an increasing number of marketing authorizations – especially for cancer drugs – have been based on single arm trials (SATs). In these studies, all patients receive the experimental treatment, and there is no control group.

At first glance, this design looks appealing. SATs are faster – thus less expensive – and may appear more acceptable to patients, since no participant is assigned to a placebo (or to standard therapy) instead of the new drug.

The idea for our article followed the publishing of the European Medicines Agency (EMA) Reflection paper on “Establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorization”, which focuses on key methodological challenges.

Yet, these challenges also give rise to ethical concerns. What does it mean to approve a new drug based on evidence from a study that lacks a control group? How can we ensure that participants’ consent is truly informed when dealing with large degrees of uncertainty about efficacy? More broadly, when is it ethically appropriate to rely on this design?

We found that, despite the increasing use of SATs, these ethical questions have so far received little attention. This made us step forward in that direction.

There are indeed some clear-cut situations where SATs may be clinically, methodologically, and ethically preferable. These includes cases where preliminary data suggest that the expected clinical efficacy is striking, or when the number of eligible patients is very limited (as in cases of extremely rare diseases), making controlled trials impractical.

However, determining in advance when such conditions apply is far from straightforward in most cases.

Accurately predicting the magnitude of a treatment’s effect before a study begins is seldom easy and it may be affected by bias. Furthermore, drawing a clear boundary between what counts as a “striking” rather than merely “moderate” efficacy might itself be open to arbitrariness.

These challenges are not just methodological – they have ethical weight. If the strength of the evidence is blurry, how can researchers be confident that SAT is the most appropriate design? And, in addition, how can patients make truly informed decisions about the pros and cons of this design?

To address these concerns our analysis emphasizes two safeguards.

First, independent, design-specific scientific and ethical review is essential to ensure that SATs are used only when genuinely appropriate, not simply as a shortcut to faster approval. Reviewers must be trained specifically in assessing SAT designs.

Second, a transparent and comprehensive informed consent process is critical to avoid confusion and mistrust potentially impacting communication of results to patients. Even when SAT design is an appropriate choice, participants should clearly understand the potential limitations associated with the study design. Causal interpretation of treatment effects, and statistical methods to quantify the size and precision of the effects, may be less reliable than in RCTs. Patients should be informed about what differences in the outcome would be expected to establish whether an intervention is effective. Although patients, especially those who have failed standard therapeutic lines, may welcome the certainty of receiving the investigational drug, they must be informed in advance that the trial might still be unable to determine between limited and no efficacy.

In the end, SATs can be a valuable option when traditional randomized trials are not feasible or appropriate, but only if their limitations are acknowledged and addressed with transparency and care. As reliance on SATs grows, it is crucial to ensure that innovation never comes at the expense of scientific and ethical integrity or of the trust that patients place in medical research.

Authors: Chiara Mannelli and Giuseppe Traversa

Affiliation: Bioethics Unit, Istituto Superiore di Sanità, Roma, Italy

Social Media: LinkedIn

Conflicts of Interest: None to declare