By: Robin Bliss, PhD, VP Strategic Consultant at Veristat
In oncology research, randomized controlled trials (RCTs) are sometimes impractical. RCTs minimize bias and allow a direct comparison between an experimental product and the selected control, providing a reliable way to demonstrate a new therapy’s benefit. However, for patients with rare or highly aggressive cancers and when there are no effective treatments available, randomizing patients to a control arm or to placebo may be unethical. In these cases, sponsors can turn to single-arm trials (SATs), where all participants receive the investigational therapy.
SATs as the primary evidence for registration applications has a successful history in oncology research, particularly for later-lines of treatment and rare cancers. A recent study published by JAMA found that between 2002 and 2021, the FDA granted approval for 176 new oncology indications based on SATs, including 116 accelerated approvals, with over half of the accelerated approvals pending post-marketing confirmation. The pending confirmations have led the FDA to reconsider the circumstances when SATs are acceptable for registrational trials in oncology.
The FDA’s Project FrontRunner initiative, launched in 2022, encourages sponsors to move promising therapies into earlier lines of treatment rather than waiting until patients have exhausted all other options. This shift places greater emphasis on randomized evidence, allowing direct comparisons of experimental treatment effect and safety to available and approved products.
The shifting regulatory paradigm creates tension, challenging researchers to evaluate the best course for their novel product to reach patients faster. While regulators are calling for more early line research and robust comparisons to available therapies, the reality is that treatments are unavailable or ineffective for many rare and aggressive cancers, making an RCT difficult, if not impossible. If designed and executed with rigor, SATs can be a strategic – even crucial – path toward regulatory approval of new treatments for patients who have no other options.
The Benefits of SATs in Oncology
There are several compelling reasons for single-arm design.
For some cancers, the populations affected are extremely small. With few eligible patients, conducting a randomized trial can be nearly impossible, particularly if multiple studies are competing for the same individuals in a single region. Because a SAT’s simpler study design removes the need for a comparison or control group, they often do not require as many participants.
Ethical considerations also play a critical role. For aggressive cancers with no approved therapy, it would be unethical to randomly assign a patient to receive placebo or to remain untreated. In SATs, every participant receives the therapy.
SATs can also offer increased speed and efficiency. Compared to RCTs, SATs typically require fewer patients, shorter timelines, and simpler logistics. This streamlined approach allows researchers to detect efficacy signals earlier and adopt a “fail fast” mindset, conserving resources if a therapy proves ineffective.
Under the right circumstances, regulatory precedent has made SATs an attractive option. Many oncology drugs have been approved through the accelerated approval pathway based on strong efficacy signals from SATs, reinforcing their value as a practical and accepted route to bringing promising treatments to patients.
The Challenges (and How to Mitigate Them)
SATs bring methodological and regulatory risks that need to be carefully considered. Some common challenges include:
Lack of a control arm
Without a randomized control arm, there is limited evidence as to whether the safety and efficacy results are due to the treatment, reflect the natural course of disease, are caused by some external factor, or occur by chance. Interpretation of study data can be strengthened by incorporating external or synthetic controls.
Limited interpretation of time-to-event endpoints
Time-to-event measures, such as progression-free or overall survival, have limited interpretability without a control arm. Regulatory agencies often view objective response rate (ORR) as a credible surrogate endpoint in SATs; however, ORR does not always correlate with extended overall survival, leading to some approvals being withdrawn. Discuss endpoint selection and criteria for success with regulatory authorities during the trial planning process.
Regulatory engagement
When planning an SAT, sponsors should approach regulatory authorities during protocol development with a description of the well-defined population and their unmet medical need, a justification for the lack of a comparator in the current treatment landscape, and potential sources of bias with mitigation strategies. Early engagement with regulatory agencies can align sponsors to the expectations of the regulatory agencies, allowing for greater transparency and opportunity for success.
Prespecified hypotheses
The scientific hypothesis to evaluate treatment effect, including statistical methods and thresholds for comparison, should be pre-specified and detailed within the SAT protocol and statistical analysis plan. Threshold value(s) for comparison of surrogate endpoints – such as a lower boundary to compare against the observed ORR – should be justified based on prior research, published data, or an external control source. Applying rigor to the study hypothesis statements and statistical methods will decrease opportunity for bias and increase confidence in the study conclusions.
Clearing Regulatory Hurdles
A sponsor developing a therapy for an ultra-rare hematologic malignancy faced a patient population too small for a randomized trial. There were no alternative treatments available, and patients were expected to have progressive disease and death within a few months following diagnosis. A Phase 1/2 dose escalation and expansion SAT was designed to evaluate an investigational therapy within the ultra-rare indication.
During the dose expansion portion of the trial, a higher-than-expected complete response rate was observed. After seeing the promising results, in collaboration with the FDA, the sponsor amended the ongoing Phase 1/2 study to add a separate, confirmatory single-arm cohort. They agreed with the FDA on a lower complete response threshold (based on literature on dire nature of the disease) that, if exceeded, would establish efficacy. Duration of response was identified as a key secondary endpoint. The separate cohort was enrolled and treated, the pre-specified threshold was exceeded, and this SAT led to a full approval of the product in the US.
The EMA was not approached for feedback or comment on the planned confirmatory cohort and modifications to the single-arm, Phase 1/2 study protocol until after study completion. This made the European marketing application review more challenging, with a greater focus on the overall study sample, where there were greater variations between patient response due in part to different amounts of time on study. The agency ultimately granted approval, but only under exceptional circumstances, requiring post-marketing commitments for further research.
The case highlights two lessons: early, parallel engagement with global regulators is essential, and aligning study design, operations, and regulatory strategy from the outset can help sponsors navigate the risks of SATs in rare disease research.
Best Practices for Single-Arm Oncology Trials
Executing a credible SAT requires careful attention across design, operations, and regulatory strategy. Some best practices include:
- Early planning: Evaluate patient pools and biomarkers to identify an appropriate population for a single-arm design, while serving as wide a population as possible.
- Endpoint selection: Carefully choose endpoints that are clinically meaningful, biologically justified, and objectively measured.
- Control strategies: Where possible, incorporate external or synthetic controls based on high-quality published, historical, or real-world data. Assess feasibility of randomized versus single-arm designs.
- Statistical rigor: Pre-specify scientific questions and hypotheses for evaluation, statistical analysis plans, and timing of data review and analysis. Include mitigation strategies for bias and the handling of missing data within the analysis plans.
- Regulatory alignment: Engage regulators early. Provide clear justification for use of a SAT, agree on data sources and statistical strategies, and include confirmatory trial plans. Involve regulatory agencies from the targeted areas for both trial execution and eventual marketing applications.
The CRO Advantage in Navigating SATs
SATs are an important tool in oncology research; however, they are not a shortcut. Success requires thoughtful design, rigorous operational and statistical planning, and careful alignment with regulatory expectations from the start.
Work with a CRO that brings deep oncology expertise and that can help transform a high-risk development path into a credible, strategically managed program. From protocol design and control-arm sourcing to statistical modeling, trial execution, and regulatory submissions, an experienced partner can help sponsors generate persuasive evidence while navigating an evolving regulatory landscape.
Cancers are complex and difficult to treat, and for many cancer types, there are limited treatment options that work. Given the dire nature of cancer – particularly among rare disease and recurrent, relapsed, or refractory settings – it may not be ethical to randomize patients to placebo or to a standard of care. When well-planned and well-executed, SATs can accelerate access to life-saving therapies that might otherwise never reach desperate cancer patients.
About the Author
Robin Bliss, PhD, is Veristat’s Vice President, Strategic Consulting where she oversees and executes strategic clinical development consulting, collaborating with regulatory, clinical and medical, and statistical teams. Bliss is experienced in planning and implementing complex study protocols, adaptive trial designs, study analyses, regulatory submissions, and providing statistical representation at regulatory agency meetings. Prior to Veristat, Bliss worked with Brigham and Women’s Hospital Orthopedic and Arthritis Center for Outcomes Research and with Boston University School of Public Health Environmental Health Department. She earned her PhD and MA in Biostatistics from Boston University and her BA in Mathematics from Williams College. She can be reached at [email protected].