Single-arm trials as pivotal evidence: Key considerations and implications for drug developers

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

The European Medicines Agency (EMA) confirmed its position on the use of single-arm trials (SATs) as pivotal evidence in marketing authorization applications. In September, it announced its adoption of the final version of the reflection paper¹, which provides critical guidance for drug developers considering SATs for their pivotal studies. While randomized controlled trials (RCTs) remain best practice, there may be situations where SATs are considered. However, using SATs could pose significant challenges and limitations that must be carefully addressed. 

In this blog post, we'll explore the six key considerations outlined in the EMA reflection paper and discuss their implications for drug developers. 

1. Justification for using SATs 

Key consideration: Using SATs as pivotal evidence deviates from the expected standard of RCTs. The EMA is signaling that it will no longer accept SATs in settings where RCTs are feasible. 

Implication: Developers must justify why a SAT is appropriate and how it can provide adequate evidence of efficacy. This justification should be based on the investigational treatment's full clinical context and attributes. 

Action: Seek early scientific advice from regulators to discuss the acceptability of SATs for your specific development program.  

2. Endpoint selection 

Key consideration: The primary endpoint in a SAT must be objectively measurable, able to isolate treatment effects (i.e., outcomes should occur only due to effective treatment), and should be clinically relevant.  

Implication: Endpoint selection is critical and more challenging in SATs than RCTs. Specific considerations for different types of endpoints include: 

• Time-to-event endpoints are generally not suitable for SATs due to difficulties in attributing outcomes to treatment. FDA has the same policy.  
• Continuous endpoints are challenging to interpret in SATs due to natural variability and potential for regression to the mean. 
• Binary endpoints may be more suitable if appropriately defined, especially if the outcome is not achievable without treatment. 

Action: Carefully select endpoints that can clearly isolate treatment effects while being clinically relevant. Consider seeking regulatory input on endpoint selection.  

3. Trial population and external validity 

Key consideration: The trial population in a SAT is critical for ensuring external validity and interpreting results. 

Implications: 

The trial population must closely reflect the intended target population. 

• Selection bias is a major concern in SATs. 
• Exploring treatment effect heterogeneity across subgroups is particularly challenging in SATs. 

Actions: Precisely predefine and justify inclusion/exclusion criteria. Document the participant selection process in detail. Consider potential prognostic and predictive factors in the trial population. Be cautious when using biomarker-defined populations in SATs. 

4. Statistical considerations 

Key considerations: 

• Pre-specification of analysis plans is crucial. Protocol amendments in open-label studies are scrutinized by the EMA.  
• A justified threshold for demonstrating efficacy should be defined a priori.  
• Proper handling of missing data is essential.  

Implications: Statistical analysis plans must be finalized before trial initiation, as the EMA will view anything else as an exploratory study and hypothesis-generating exercise. The choice of efficacy threshold should reflect uncertainties associated with external information. KOL input is important. Sensitivity analyses are crucial to support the robustness of estimates. 

Actions: Invest in thorough statistical planning before trial initiation. Prespecify methods for handling missing data and conduct sensitivity analyses. Consider multiple distribution scenarios when incorporating covariates in analyses. 

5. Bias mitigation 

Key consideration: SATs are particularly susceptible to various forms of bias. 

Implications: Multiple potential sources of bias must be addressed throughout the design, conduct, analysis, and reporting of SATs. 

Actions: 

Implement strategies to mitigate 

• Assessment bias: Use objectively measurable endpoints and consider blinding assessors. Use primary endpoints that are supported by EMA, but are also supported by secondary endpoints, e.g., CR as a primary endpoint cannot be standalone in r/r AML. Support from clinically relevant secondary endpoints, e.g., transfusion independence, will be critical.  
• Attrition bias: Minimize missing data through trial design and conduct.  
• Bias due to lack of pre-planning: Finalize plans before trial initiation and minimize post-initiation changes. Protocol amendments in open-label are in general scrutinized by the EMA, and often lead to GCP inspections.  
• Regression to the mean: Avoid selection based on extreme values. 
• Selection bias: Precisely prespecify inclusion/exclusion criteria and document selection processes. 
• Intercurrent event bias: Anticipate and plan for intercurrent events. 

6. Estimating treatment effects 

Key consideration: Estimating treatment effects and their uncertainty is more challenging in SATs than RCTs. 

Implications: Only results under the investigational treatment are observed. Assumptions about the natural course of disease are critical, but often neglected by sponsors.  

Action items: Clearly define the counterfactual treatment condition. Gather robust external data on the natural course of disease. A preplanned RWE study may be key to success. Any RWE study planned/executed after data readout risks being perceived by the EMA as selective data use.  

Conclusion 

While SATs may be appropriate in certain scenarios, they have significant challenges and limitations. The EMA is tightening the requirements for SATs, and is going to ensure drug developers justify the use of them. Drug developers considering SATs as pivotal evidence should: 

• Engage early with regulators to discuss the acceptability of SATs for their specific program. 
• Invest heavily in trial design, focusing on endpoint selection, population definition, and bias mitigation. 
• Develop robust statistical analysis plans that address the unique challenges of SATs. 
• Gather strong external data to support assumptions about the natural course of disease. 
• Be prepared to provide comprehensive justification for using SATs instead of RCTs. 
• Consider SATs as part of a broader evidence-generation strategy, potentially complemented by other study designs or real-world data. 

By carefully addressing these considerations, developers can improve their chances of successfully using SATs as pivotal evidence. However, they should always be aware of the inherent limitations and be prepared for additional scrutiny from the EMA. 

As a leading global phase I-IV clinical research organization, we leverage the breadth of our clinical, regulatory and therapeutic expertise to optimize clinical development programs. Our team of ex-regulators is always available to help you navigate the regulatory requirements of the major regulatory agencies, including an assessment of this new reflection paper. Parexel’s Regulatory Consulting group interprets evolving regulatory requirements, prepares robust submissions, and effectively manages interactions with regulatory agencies, ultimately helping to bring innovative therapies to patients more efficiently and effectively. Please contact us.   

References: 

European Medicines Agency (2024, September 16). Establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorization:  
Establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation | European Medicines Agency (EMA) (europa.eu) [accessed September 20, 2024] 

Return to Insights Center