Emerging biopharma companies are driving some of today’s most promising advances in oncology, but many face constraints (i.e., ethical, rare populations) that make it difficult to run fully powered randomized controlled trials (RCTs), and are instead relying on single-arm trials to generate evidence. But is a single-arm trial enough to get a new treatment to market?
While the FDA has historically accepted single-arm trials as the basis for accelerated approval in certain settings, particularly in oncology and rare diseases, other regulators, including the EMA, have taken a more cautious view of single-arm evidence. The EMA has stated that randomized controlled trials are the regulatory standard and that deviations using single-arm trials require justification. Even when the FDA Pgrants accelerated approval based on a single-arm trial, confirmatory evidence is generally required.
Whether you plan to bring a new treatment to market in the U.S. or abroad, establishing a rigorous comparator early can make results easier to contextualize, strengthen the overall evidence package, and help address regulatory expectations. Advances in data availability, data quality, analytic methods, and regulatory guidance have made external control arms (ECAs) an increasingly viable option for contextualizing single-arm trial results and generating comparative evidence. For emerging biopharma, their value can extend well beyond regulatory submission, supporting critical decision-making throughout the development lifecycle.
So what makes ECAs particularly attractive for emerging biopharma? Where can they add the most value? And why is data quality non-negotiable?
Why emerging biopharma needs ECAs
For emerging biopharma companies, every development decision carries outsized strategic and financial weight. Limited resources and tight timelines leave little room for studies that fail to demonstrate clear benefits.
At the same time, the patient populations these companies often serve can make traditional RCTs impractical. Rare diseases and molecularly defined populations can limit recruitment, for instance, while rapidly evolving standards of care can make it difficult to establish a standard comparator. In some settings, randomization can be hard to justify for ethical reasons too.
Single-arm trials offer a viable path forward, but without an appropriate comparator, interpreting their results and meaningfully contextualizing their outcomes can be difficult. An ECA provides a way to put those results into context by showing how a comparable population fared under existing care.
For emerging biopharma, that puts ECA planning front and center. With Clinical Development, Biostatistics, Regulatory, and Medical Affairs teams working together from the outset, they can immediately align on the study population, endpoints, follow-up period, and other key criteria needed to construct a credible external comparator.
Where ECAs create value
The value of an ECA extends well beyond regulatory submission.
Early in development, ECAs can help establish standard of care benchmarks that, when run in parallel with other evidence generation studies, support feasibility assessment, trial design, endpoint selection and ultimately go/no-go decisions. Later, they can help contextualize single-arm results for accelerated approval or marketing authorization and provide supportive comparative evidence for Health Technology Assessment (HTA) bodies. ECAs also offer an important benchmark when a product receives accelerated approval and control arm patients crossover to the treatment arm, making endpoints like OS difficult to interpret. In these cases, ECAs provide a standard of care data for evaluating treatment arm outcomes.
Alongside the development cycle, comparative evidence from ECAs strengthen the scientific credibility of an emerging development program by making single-arm findings more interpretable for peer-reviewed publications, scientific and clinical audiences, and investors.
The key is to start with fit-for-purpose data and methods that can support increasing evidentiary demands as the program progresses. An ECA built this way can deliver useful insights early in development while providing a credible foundation for regulatory and HTA needs later.
Why validated, fit-for-purpose data is non-negotiable
Not all RWD is suitable for building an ECA. As regulators increasingly consider RWD for decision-making, the emphasis is shifting from simply having enough data to demonstrating that the data is accurate, complete, traceable, and fit to answer the research question. After all, a dataset that is fit for one question may not be fit for another.
For an ECA in today’s regulatory environment, that distinction is paramount. Research teams need to scrutinize data provenance, extraction processes, quality controls, and ensure that the analysis can be adequately audited and reproduced. These are not technical details to address just before submission; they’re an integral part of the evidence supporting the credibility of the comparator itself.
Clinical depth matters, too. Missing or inconsistently captured biomarkers, performance status, treatment history, or clinically validated real-world endpoints (such as rwOS and rwPFS) can affect everything from cohort definition to confounding adjustment. If key prognostic factors are poorly captured, even sophisticated statistical methods may not be able to compensate.
Data recency is another critical consideration in oncology, where standards of care and treatment patterns can change rapidly. An external population drawn from outdated data may no longer represent the patients or treatment landscape relevant to the trial. Contemporaneous RWD might be essential to establishing a meaningful comparison.
For sponsors, the implications are clear: document why the data is fit for purpose when the study is designed, treat data provenance, quality control, and processes as part of the evidence package, and engage health authorities early to confirm that they’re aligned with the proposed data and study design.
Building ECAs with confidence
For emerging biopharma, external control arms can provide a practical tool to generate the comparative evidence that single-arm trials cannot provide on their own. They can inform decisions throughout development, strengthen the interpretation of clinical results, and support regulatory and market-access strategies.
But the value of an ECA depends on the strength of the evidence behind it. Fit-for-purpose data, rigorous methods, and early planning are essential to building a comparator that can stand up to scrutiny.
That’s why it’s important to partner with a company with access to rich, comprehensive, regulatory-grade RWD and deep expertise interfacing with regulatory authorities around the world. At Flatiron, we've worked with the FDA’s Oncology Center of Excellence since 2016 to help evaluate the role of real-world evidence in a regulatory context, and in recent years, we’ve supported submissions of ECA-based comparative evidence to health authorities across Europe and Japan. That work has shaped a practical, phased approach to developing effective ECAs in partnership with emerging biopharma companies like yours.
Check out our new playbook for more details: Building external control arms with confidence — a playbook for emerging biopharma, and reach out below to connect with our regulatory experts to explore whether an ECA is right for you and learn how we might be able to support study design and execution.
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