EMA's Take on Single-Arm Trials: Key Insights for Regulatory Success

The pharmaceutical industry has shown a growing interest in single-arm trials due to their potential to expedite drug development. However, several challenges and concerns remain.

The European Medicines Agency (EMA) has recently released a reflection paper on the establishment of efficacy using single-arm trials as pivotal evidence in marketing authorization applications (MAAs). While randomized controlled trials (RCTs) remain the gold standard for clinical efficacy assessment, the EMA acknowledges the growing role of single-arm trials in certain therapeutic areas, particularly when RCTs are unfeasible.

This blog delves into the highlights of the reflection paper, outlining key considerations for single-arm trial design and execution, and how ProPharma can support Sponsors in navigating these complexities in light of regulatory decision-making.

The Context for Single-Arm Trials

Single-arm trials evaluate the efficacy of investigational treatments without a formal comparison group. They are valued for their ability to deliver faster results with smaller sample sizes and lower costs. This is particularly advantageous in the development of drugs to treat rare diseases or urgent medical needs where patient populations are limited. In scenarios where withholding treatment from a control group would be unethical, single-arm trials provide a viable alternative. This is especially pertinent in life-threatening conditions where effective treatments are urgently required.

However, due to the lack of parallel control groups, many confounding factors are difficult to manage and due to the significant methodological challenges, the conclusions of the trials may be difficult to interpret. 
While the gold standard for evidence generation in pivotal trials remains RCTs, single-arm trials may be considered in certain circumstances where the feasibility of an RCT is limited. This is the case when for example:

• The clinical condition is rare
• Ethical considerations preclude the use of a control group

Should a single-arm trial for pivotal evidence generation be considered, justification for its use would need to be provided within the marketing authorization application. As part of such justification, it must be substantiated that the single-arm trials provide adequate pivotal evidence of efficacy. The EMA recommends extensive consultations to ensure methodological appropriateness via for example, scientific advice.

Critical Considerations in Single-Arm Trial Design

When considering a single-arm trial for future pivotal evidence generation, there are several considerations that are specific to a successful design and will need ample consideration and reflection. Some of these considerations are listed below.

1. Choice of Endpoints

Endpoints must isolate treatment effects unequivocally, especially in the case of a single-arm trial. Any uncertainty as to whether observed individual outcomes are undoubtedly caused by the treatment complicates the interpretation of results from a single-arm trial. As such, endpoints in single-arm trials must be chosen with ample care. For example:

• Binary endpoints such as cure rates may be appropriate for conditions with negligible spontaneous recovery.
• Continuous and time-to-event endpoints are generally less suitable due to their vulnerability to natural variability and lack of control for prognostic factors.

2. Bias Mitigation

Single-arm trials are particularly prone to bias due to their lack of parallel control groups; the EMA’s reflection paper identifies potential biases that would need to be taken into consideration, including:

• Assessment bias: ensure objective and blinded outcome assessments
• Selection bias: thoroughly define and document inclusion and criteria to ensure representativeness
• Attrition bias: employ rigorous data management to minimize missing data

3. Target and Trial Population

The trial population must align closely with the target population to ensure external validity. Careful selection and documentation of participants are critical to address potential biases in disease prognosis and treatment response.

4. Statistical Rigor

Single-arm trials face unique challenges due to the absence of a control group, necessitating rigorous

• Threshold Setting: Defining efficacy thresholds is critical but challenging, as these rely on external data prone to uncertainty. Conservative and prespecified thresholds are essential to avoid overestimating treatment effects.
• Analysis Principles: All analyses must be prespecified, including methods for handling intercurrent events and missing data, to ensure unbiased and reliable results.
• Sensitivity Analyses: Conducting sensitivity analyses is vital to assess the robustness of assumptions, particularly regarding the natural disease course and covariate handling.
• Multiplicity and Sample Size: Careful planning is needed to address multiple endpoints or interim analyses and ensure sufficient sample size for reliable conclusions.

5. Regulatory Alignment

While the EMA’s reflection paper provides a framework for single-arm trials, gaining regulatory acceptance remains a challenge. Sponsors are encouraged to maintain early and continuous dialogue with regulatory bodies to align trial design with regulatory expectations, ensuring endpoints, thresholds, and analyses are acceptable.

Transform Your Single-Arm Trials and Achieve Successful Regulatory Interactions with a Global Regulatory Partner

While single-arm trials present unique challenges, their strategic application in rare or ethically constrained scenarios is invaluable. EMA’s reflection paper provides a long-awaited framework for their use, emphasizing the importance of methodological rigor and bias mitigation.

ProPharma's extensive experience and unique, tailored approach make us the ideal partner for pharmaceutical companies considering single-arm trials. Our team of expert regulatory consultants possess extensive scientific knowledge; coupled with our expertise in regulatory affairs, trial design, patient support, and strategic alignment, we ensure that our clients can confidently navigate the complexities of single-arm trials and optimize their chances of successful market authorization.