As payers and HTA bodies increasingly demand robust comparative evidence beyond what single-arm trials can provide, real-world external control arms (RW-ECAs) have become a pragmatic approach to bridge critical evidence gaps when randomized controlled trials (RCTs) are impractical or unethical. By leveraging observational cohorts from claims data, registries, or electronic health records, RW-ECAs can provide robust comparative insights to support health technology assessment (HTA) submissions. In this post, we explore the opportunities and challenges inherent in these designs, outline methodological best practices to withstand payer scrutiny, and highlight Putnam’s proven capabilities in delivering fit-for-purpose RW-ECA evidence.
A real-world external control arm is an observational cohort derived from real-world data (RWD) that functions as a non-concurrent, non-randomized comparator for a single-arm trial. The foundation of any RW-ECA rests on four pillars:
Together, these pillars ensure that an RW-ECA emulates the design rigor of a randomized trial, bolstering the credibility and robustness of comparative effectiveness estimates derived from real-world data.
Traditional RCTs remain the gold standard for HTA, but they pose significant hurdles in rare diseases, ultra-small pediatric populations, or scenarios where placebo-controlled designs may be deemed unethical. Single-arm trials are increasingly used as pivotal evidence in HTA submissions. Between 2019 and 2024, 18 NICE submissions incorporated RW-ECAs, 16 in oncology, one in cardiovascular, and one in rare disease settings. 1 Further, there has been a 20% increase in RW-ECAs submitted to global HTA agencies between 2018-2019 compared to 2015-2017, underscoring growing payer receptivity to these designs. 2
To withstand payer and regulatory scrutiny, RW-ECA designs should emulate a “target trial” framework:
By implementing these elements in a transparent statistical analysis plan and reporting per accepted guidelines, sponsors can proactively address committee and evidence review group critiques and bolster the credibility of the RW-ECA evidence. The figure below illustrates key methodological considerations in RW-ECA design, spanning data curation, adjustment strategies, and quantitative bias analyses.
In a recent Putnam RW-ECA study led by our RWE & Biostatistics team, we emulated a target trial to compare outcomes from a single-arm olutasidenib trial against an external RWD cohort of patients receiving ivosidenib for relapsed or refractory modified IDH1 acute myeloid leukemia post-venetoclax.3 By applying entropy balancing, prespecifying all eligibility and follow-up criteria including estimands, and conducting sensitivity analyses, the study demonstrated how robust confounder control and transparent estimand specification can deliver credible comparative estimates even when sample sizes are constrained.
Opportunities
Challenges
While RW-ECAs offer significant advantages, they also introduce unique hurdles that must be proactively managed:
By recognizing these challenges up front and embedding fit-for-purpose mitigation strategies in the study protocol and analysis plan, a well-specified RW-ECA, can accelerate regulatory and HTA timelines, support label expansions, and ultimately expedite patient access to breakthrough therapies.
Real-world external control arms represent a strategic imperative for pharmaceutical sponsors navigating the complexities of HTA in rare or single-arm trial settings. By adhering to a robust target trial emulation framework, implementing quantitative bias analyses, and implementing a mitigation strategy for the possible analysis challenges, compelling, payer-ready evidence that accelerates patient access can be generated.
At Putnam, we partner with clients to translate methodological best practices into operational success, delivering evidence that not only meets but anticipates HTA expectations.
Our RWE & Biostatistics team will also be showcasing a recent related study at ISPOR Europe 2025 in Glasgow. Our abstract, ‘Influence of NICE Real-World Evidence Framework on HTA Submissions: Sensitivity Analyses in Real-World External Control Arm Studies,’ has been accepted as a Top 5% poster presentation. This recognition underscores the team’s leading role in advancing best practices for RW-ECAs and highlights our deep expertise in applying sensitivity analyses and quantitative bias analysis to address payer and regulator concerns. To explore how we can support your next RW-ECA submission, please reach out to our RWE & Biostatistics team contact us.
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