When can single-arm trials support drug filings?

The EMA has launched a consultation on the circumstances in which single-arm trials (SATs) – those without a control group – can be used to support marketing applications for medicines in the EU.

To kick off the deliberations, the regulator has published a reflection paper covering the overarching concepts behind single-arm trials, and launched a consultation period due to conclude at the end of September.

Generally, any new treatment should be tested with a randomised controlled trial (RCT), where it is compared to either a placebo or an alternative therapy – often without either the physician or patient knowing which is which – in order to reduce the risk of bias skewing the results.

SATs tend to be used for diseases, such as cancer, where patients have become relapsed and refractory to earlier therapies, as well as in rare diseases where having a placebo control group may not be ethical or feasible.

The EMA’s move comes a few weeks after the FDA published draft guidance on the design of clinical trials used to support filings for accelerated approval of cancer drugs, which revealed a clear preference for RCTs with a control arm, with SATs only acceptable if a randomised design is not feasible.

The move by the US regulator addresses concerns that new medicine developers using the early access pathway have sometimes been lax in carrying out subsequent trials need to confirm the efficacy of their drugs.

In a statement, the EMA said its new paper is designed to “stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct.”

The main thrust of the document is demonstrating the efficacy of therapies, although the EMA notes that “establishing safety via SATs is fraught with substantial shortcomings, and many of the critical considerations discussed equally apply to the assessment of safety.”

The paper covers the choice of endpoints that should be considered for SATs, how to make sure target and trial populations are selected appropriately, the statistical approaches to interpreting the data, and how external information, such as general knowledge about the natural history of a disease, can be used in a study protocol. It also discusses the sources of bias that can creep in and provides possible ways to mitigate them.

Finalised guidance is expected next year, after an analysis of received comments, said the EMA.