Single-Arm Studies: A Strategic Path to Oncology Drug Approval

In oncology drug development, randomized controlled trials (RCTs) are the gold standard for generating data to secure regulatory approval. The recent FDA Project Frontrunner (to read more about Veristat’s thoughts on Project Frontrunner, click here) emphasizes the importance of evaluating new treatments in earlier disease settings. This provides the opportunity for a larger number of patients to have access to new products and an opportunity for a direct comparison of new investigational products to established approved therapies through RCTs. In some situations, however, an RCT is not the most appropriate study design. The single-arm trial can provide a fast and feasible route while still producing persuasive evidence of a treatment’s benefit.

Robin Bliss, PhD, Vice President of Strategic Consulting at Veristat, has guided numerous sponsors through the study design selection process, including the decision of whether they can use single-arm trials as registrational studies. Her insights reveal when and how this design can accelerate the path to market.

Why Single-Arm Trials Matter in Oncology

In RCTs, participants are assigned to either the investigational treatment or a control group, often a placebo or standard of care. While scientifically rigorous, this design can be time-consuming, costly, and sometimes unethical.

In a single-arm trial, all participants receive the investigational therapy. This design can:

• Accelerate access, bringing promising treatments to patients sooner when they have no other treatment options.

• Require fewer participants, enabling studies in rare or severely ill populations.

• Identify efficacy signals early, supporting quicker go/no-go decisions in early phase studies.

Such trials are especially relevant when the patient population is small, disease progression is rapid, or withholding treatment would be unethical.

When Single-Arm Trials Are Appropriate

Below are three common scenarios where single-arm designs can be effective:

• High unmet medical need – No approved therapies or ineffective first-line options.

• Rare or severe disease sub-populations – RCT recruitment may be impractical.

• Rapid, durable responses expected – The investigational therapy shows potential for clear, meaningful benefit.

Despite these advantages, there are limitations in the conclusions that can be made from single-arm studies, particularly because there is not a direct comparison to a control arm to demonstrate efficacy or safety of the investigational product.

Designing a Strong Single-Arm Trial

To use a single-arm trial as a registrational study in the U.S. or EU, careful preparation is essential. At Veristat, we advise sponsors begin with:

1. Defining the target population – Who stands to benefit most?

2. Evaluating the treatment landscape – How do existing therapies perform?

3. Identifying comparators – External or historical data may help contextualize outcomes.

With these in place, four technical pillars shape success:

1. Choosing the Right Endpoints

Overall survival is the ultimate measure of clinical benefit, but without a control group, survival outcomes are difficult to interpret as identifiers of product efficacy or safety. Surrogate endpoints such as objective response rate can be observed earlier than overall survival, are unlikely without intervention, indicate a positive patient outcome, and can be directly compared against historical rates with appropriate considerations for sources of bias.

2. Controlling Bias

Bias is a top regulatory concern. Strategies include finalizing the protocol and analysis plan before trial start, pre-specifying data reviews, and using an independent review committee for outcome assessments, such as reading tumor assessment images.

3. Setting Sample Size

While smaller than RCTs, the sample size should still be large enough for precise estimates of efficacy and safety. It is important to recognize that a few outlier patients in a small sample can disproportionately influence results. Planning to enroll a representative sample of the underlying patient population is an important consideration to provide the most generalizable results to the target population.

4. Demonstrating Clinical Benefit

Instead of outperforming a concurrent control, the trial should exceed a predefined threshold for the identified efficacy endpoint. For example, if standard care yields a 5% response rate, the new therapy might aim for 20% or higher, with a lower bound still meeting clinical significance. Similar parameters can be determined around safety events.

Working with Regulators

While both the FDA and EMA prefer RCTs, they have approved oncology drugs based solely on single-arm trial data—31% of FDA approvals from 2002–2021 and 27% of EMA approvals from 2012–2021.

The value of early, ongoing dialogue with regulators cannot be overstated. These conversations can clarify expectations, uncover challenges, and allow proactive adjustments before costly delays.

Advantages and Trade-Offs of Single Arm Studies

Advantages:

• Opportunity for faster completion and earlier regulatory submission.

• Feasible in small or hard-to-reach patient populations.

• Ethical in settings where withholding treatment is unacceptable and no alternative treatments exist.

Limitations:

• Smaller safety datasets.

• More complex interpretation of results without a control arm.

• Higher susceptibility to bias.

Pathway to Approval

A focused set of strategic actions can greatly improve the chances of success:

1. Identify a compelling unmet need. Focus on patient populations with few or no treatment options.

2. Select endpoints carefully. Use measures that can reliably demonstrate benefit within the trial constraints.

3. Mitigate bias rigorously. Stick to the protocol, plan analyses in advance, and use independent reviews when appropriate.

4. Engage regulators early. Incorporate feedback before finalizing the study design.

5. Work with experienced partners. Expertise in both regulatory and statistical domains can make a decisive difference.

Single-arm trials are not universally appropriate, but in the right context they can provide the fastest route to delivering life-saving oncology treatments. Their success depends on thoughtful design, strong bias control, strategic endpoint selection, and early regulatory collaboration.

As Robin Bliss summarizes, the winning formula is “a well-designed study with a defined patient population, active conversations with regulatory agencies, and a solid understanding of the treatment landscape.”

With these elements in place, single-arm studies can transform innovative cancer therapies from promising ideas into approved treatments, getting them to the patients who need them most.

Would you like insight into determining whether a single arm study is right for your program?

Our experts can help. Contact us to arrange a call:

Robin Bliss, PhD

Vice President, Strategic Consulting, Veristat

Robin Bliss, PhD, joined Veristat in 2011, and is currently Vice President, Strategic Consulting. In her role, Robin oversees and executes Strategic Clinical Development Consulting, collaborating with Regulatory Consulting, Clinical and Medical Consulting, and Statistical Consulting.

Learn More:

• FDA’s Project FrontRunner Explained

• Aligning with FDA’s Project FrontRunner

• Single-Arm Studies for Use as a Registrational Study in Oncology