You’ve conducted a Single Armed Trial and Now Regulators Are Asking Questions

Too many biotechs unfortunately find themselves in this situation. You’ve run your single-arm trial (SAT), often with the best intentions, to get answers faster, to conserve resources, or because a randomised controlled trial (RCT) felt unfeasible or unethical for your specific patient population. And now, regulators from the FDA or EMA are knocking, armed with some rather pointed questions. It’s a high-stakes moment, your pivotal data package under intense scrutiny.

This isn’t about casting blame or saying SATs are always wrong. It's about acknowledging that when you choose this path for a label-enabling study, you're knowingly taking on a higher evidentiary burden. And when those regulatory questions land, a reactive, defensive posture won’t cut it. You need a proactive, strategic, and evidence-based response. So, what do you do now?

The Regulatory Reality Check: Lessons from the EMA (and FDA Parallels)

First, let’s ground ourselves in what regulators expect. As we detailed in our previous Inovia Bio post, "The EMA vs Single-Arm Trials: 10 Lessons from the EMA Reflection Paper", the European Medicines Agency has been quite clear about its stance. That reflection paper wasn’t just a theoretical exercise; it laid out a framework for when and how SATs might be acceptable, and the significant hurdles involved.

Key takeaways from that EMA guidance – which often mirror the fundamental concerns of the FDA, even if expressed in different documents include:

1. A High Bar for Efficacy: The treatment effect observed in an SAT needs to be substantial, durable, and ideally, represent a major therapeutic advance, especially in diseases with high unmet need and no satisfactory treatment options. Marginal gains are incredibly hard to justify without a comparator.
   
   
2. The Imperative for External Context: Since there's no internal control group, the onus is on you to provide robust external context. How does your drug's performance compare to the natural history of the disease or outcomes with existing treatments? This is where the questions often start.
   
   
3. Bias is a Major Concern: SATs are inherently prone to various biases (selection bias, assessment bias, confounding by indication). Regulators will scrutinise how, or if, these have been addressed.
   
   
4. Endpoint Selection is Critical: The chosen endpoints in an SAT must be objective, clinically relevant, and less susceptible to bias. Time-to-event endpoints, for example, are notoriously difficult to interpret without a concurrent control.

The fundamental challenge regulators face with SATs is attributing the observed outcomes solely to your drug. Without that randomised comparison, they need to be deeply convinced that the effect is real, that it's not just due to patient selection, the natural course of the disease, investigator enthusiasm, or other confounding factors. Their questions are designed to probe every aspect of this attribution.

Facing the Music: Deconstructing the Regulatory Questions

When regulators come back with questions on your SAT submission, they're not just being difficult. They are trying to bridge the evidentiary gap left by the absence of a concurrent control. Typically, their questions will revolve around:

• Natural History/Standard of Care Outcomes: What would have happened to these patients, or a similar group of patients, without your investigational drug? How does your drug's effect compare?
  
  
• Magnitude and Attributability of Effect: How large is the treatment effect, and how confident can we be that it’s truly due to your drug and not other factors (e.g., selection of patients with better prognosis, concomitant medications, spontaneous improvement)?
  
  
• Representativeness of Your Trial Population: How similar are the patients in your SAT to the broader patient population who might receive this drug if approved? Were there selection biases that might have inflated the apparent effect?
  
  
• Robustness and Clinical Relevance of Endpoints: Are your endpoints objective? Are they truly meaningful to patients? How were they assessed?

Your first step is to stop, breathe, and categorise these questions. Are they primarily focused on demonstrating the extent of efficacy, the generalisability of your findings, or perhaps the safety profile in the context of observed outcomes? Understanding the themes behind their questions is crucial for structuring your response.

Your Action Plan: Concrete Steps to Prepare and Respond

This is where you move from defence to a proactive, evidence-based strategy. Panic is not an option; a clear plan is.

• Step 1: Don't Dig In – Objectively Assess the Gaps (Gap Analysis Mindset) 
  Before you even think about responding, conduct a brutally honest internal assessment. Take each regulatory question and map it against your existing SAT data package. Where are the clear evidential weaknesses they're pointing to? What can your current data support, and where does it fall short? This isn't about admitting defeat; it's about understanding the terrain.
  
  
• Step 2: Maximise Your Existing SAT Data (The Internal Deep Dive) Can you squeeze more meaning from what you already have? Are there pre-specified subgroup analyses (be wary of post-hoc dredging, which regulators will see through) that might shed light on specific patient populations or address particular concerns? Is there longer-term follow-up data available from your SAT that adds important context on durability or late-emerging safety signals? Ensure every piece of your existing data is presented as clearly and robustly as possible.
  
  
• Step 3: The Proactive Real-World Evidence (RWE) Offensive (Building Essential External Context) 
  This is often your most powerful lever now. If you haven't already got a comprehensive RWE strategy supporting your SAT, the time to deploy one is immediately. Regulators need context, and RWE is your primary tool for providing it.
  • Constructing an External Control Arm (ECA): This is a common consideration. Can you identify and analyse data from a comparable cohort of patients (from EHRs, registries, prior clinical trials) who were not treated with your investigational drug? This is methodologically challenging and requires sophisticated approaches (e.g., propensity score matching or weighting, careful selection of outcomes and covariates, thorough assessment of baseline comparability, and addressing potential unmeasured confounders). While not a perfect substitute for a randomised arm, a well-conducted ECA can provide crucial comparative context. Be transparent about its limitations.
    
    
  • Robust Natural History Studies: Use RWE to clearly and quantitatively describe the natural history of the disease in an untreated or conventionally treated population that closely matches your SAT participants. What are their typical outcomes, progression rates, and survival patterns? This helps benchmark the results observed in your trial.
    
    
  • Comparative Benchmarking: How do the outcomes observed in your SAT (e.g., response rates, duration of response, survival metrics) stack up against published literature or RWE-derived outcomes for existing therapies or historical cohorts? Again, careful adjustment for differences in patient populations and study characteristics is essential.
    
    
• Step 4: Refine Your Narrative and Quantify Uncertainty (The Story and the Caveats) 
  Your response needs to be more than just a data dump. Craft a clear, compelling narrative that directly addresses each regulatory concern, thoughtfully integrating your SAT data with any newly generated RWE. Importantly, acknowledge the inherent limitations of an SAT and any external comparisons. Use sensitivity analyses (e.g., tipping point analyses for unmeasured confounding) to demonstrate how robust your conclusions are under different assumptions. Showing you understand the uncertainties builds credibility.
  
  
• Step 5: Plan Your Regulatory Interaction Strategy (The Engagement Plan) 
  This isn't just about sending documents; it's about a dialogue.
  • Clearly identify who will lead the technical and strategic aspects of the interaction.
  • Develop core messages that are consistent, data-supported, and directly responsive to the regulators' questions.
  • Be prepared not just to present, but to listen and discuss. Show that you understand their perspective and have made a good-faith effort to provide the best possible evidence to address their concerns.
  • If you're navigating particularly complex issues, engaging SMEs who have experience with these specific scenarios can be invaluable.

The "Too Late is Better Than Never" RWE Approach

Ideally, robust RWE generation to support an SAT begins before the trial even starts, informing its design and planning for contextualisation. However, if you find yourself in this reactive scenario, launching well-designed, rapid RWE studies to generate essential comparative or natural history data now is far better than facing regulators armed only with the uncontextualized SAT results. Modern tech-bio partners (like Inovia), with platforms designed for speed and rigour in RWE analysis, can be crucial here, turning around critical insights much faster than traditional methods might allow.

Navigating the Storm with Evidence and Strategy

Receiving challenging questions from regulators after submitting a single-arm trial is undeniably a serious hurdle. It signals that the evidentiary bar for your drug, based on the SAT alone, has not yet been met in their eyes. However, it’s not automatically the end of your programme.

A proactive, transparent, and methodologically sound response, particularly one that leverages robust real-world evidence to build the necessary external context and directly address specific regulatory concerns, offers the most constructive path forward. It’s about demonstrating to regulators that you acknowledge the limitations of your single-arm study and have rigorously worked to provide the comprehensive evidence package they need to assess your drug's true value and place in therapy. Your ability to do this effectively can make all the difference.