Strategies for externally controlled single-arm trials

In support of approval for drug development sponsors, real-world evidence (RWE) scientists within Fortrea Consulting have interpreted the U.S. Food and Drug Administration’s (FDA’s) guidance document, “Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products.”

The team recently published a white paper outlining the critical aspects of single-arm trials that use real-world data (RWD) to support an external control arm (ECA). An ECA may be necessary due to ethical and/or design challenges, such as in rare disease trials where the number of eligible patients is likely very small or in oncology trials where the use of a placebo may not be ethical.

A single-arm trial consists of patients who are enrolled and followed up prospectively as they receive the investigational therapy. Such trials enable assessment of the efficacy and safety in absolute terms (i.e., not directly compared to either a placebo or a reference therapy). For this reason, such trials do not directly provide comparative evidence of the benefit of the investigational therapy. Despite this drawback, an increasing number of single-arm trials are being proposed to support the application of new therapies.

An externally controlled trial is one in which the control group consists of patients who are not enrolled in the trial. The endpoints in patients receiving the investigational therapy are compared to endpoints in patients external to the trial who did not receive the therapy. Patients in the ECA must be similar to the enrolled patients based on certain characteristics.

The white paper highlights some of the design and analytical challenges that warrant careful consideration such as:

• Designing an ECA for a single-arm trial by identifying and addressing potential sources of bias
• Understanding the important intercurrent events, which may affect the interpretability of the endpoints
• Evaluating assumptions in a statistical analysis plan’s proposed approach

We invite you to read the white paper to understand how to better inform decisions at the planning stages of a single-arm trial with an ECA.

Please also join us at ISPOR Europe 2024, November 17-20 in Barcelona, Spain, where we present our poster with a checklist for assessing the viability of an ECA for a single-arm trial.

For more on Fortrea's experience in regulatory strategy consulting, visit https://www.fortrea.com/solutions/fortrea-consulting-services/market-access-consulting-and-heor.html