One Pivotal Trial, Higher Stakes: Why Real World Evidence Matters More Than Ever

For decades, the FDA’s interpretation of “substantial evidence”—typically demonstrated through two adequate and well-controlled trials—served as the backbone of regulatory certainty that a therapy could improve clinical outcomes with acceptable safety. However, the FDA recently announced that one pivotal trial, supported by fit-for-purpose confirmatory evidence, will now be the default pathway for FDA approval of novel products.  

This change does not lower the evidentiary standard for safety and efficacy. Instead, it places greater weight on that single pivotal trial, increasing the importance of rigorous study design, execution and evidence generation. It also signals a growing opportunity to use real world evidence (RWE) to inform strategic decisions much earlier in the drug development lifecycle. 

In areas such as oncology and rare disease, regulators have long demonstrated flexibility when therapies address significant unmet need, show substantial treatment effect, or are supported by one adequate and well-controlled investigation that is sufficiently persuasive and supported by credible confirmatory evidence. Single trials have, in fact, supported the majority of oncology drug approvals: a 2026 meta-analysis published in The Oncologist found that 87% of FDA-approved cancer pharmacotherapies were approved on the basis of a single pivotal study. But what was once concentrated in a limited set of therapeutic areas is now becoming more relevant across the broader development landscape. 

What happens in a one-pivotal-trial environment is that risk gets concentrated into the proverbial “one shot on goal.” Whether developing therapies in oncology, rare disease, neuroscience, immunology or other disease categories, sponsors now face far greater scrutiny on trial design, patient selection, endpoints and analytic rigor. There is less margin for error, fewer opportunities to course-correct and greater pressure to make the right strategic decisions earlier in development.  

This is Where RWE Becomes Critical to Clinical Trial Design Strategy 

Now, with success (or very costly failure) hinging on just one pivotal trial, RWE becomes even more important. Sponsors must deeply understand the real-world patient population before initiating a trial, not after approval. That means using properly vetted RWD to generate insights about who actually receives treatment in practice, including diverse populations, patients with comorbidities and those often underrepresented in traditional trials. Without this understanding from day one, a single trial risks missing key safety or efficacy signals that might only emerge in broader populations.  

To avoid these pitfalls, RWD must be rigorously analyzed to generate fit-for-purpose, credible evidence that can both withstand regulatory scrutiny and—especially for small and emerging biotech companies—build investor confidence. 

Endpoint Strategy is Another Area Where Drug Development Risk is Amplified 

Clinical trials do not always fail because a therapy lacks promise. Sometimes they fail because endpoints are misaligned with how disease progresses in real-world settings or because they do not adequately capture outcomes that matter to patients, clinicians, regulators or payers.  

In other cases, it’s because regulators consider the endpoint is too nebulous or hard to measure. Or the endpoint is based on an assumption—about the significance of a specific genetic mutation, for example—without considering the more complex picture surrounding it. RWD helps mitigate this risk by identifying meaningful, measurable endpoints based on prior evidence, actual patient journeys and treatment patterns.  

Innovative Predictive Models Can Test Assumptions 

Another emerging application of RWD is the use of data-driven modeling and simulation approaches to evaluate key trial design assumptions before a pivotal study begins. Using epidemiologic and statistical methods, sponsors can simulate different design choices, evaluate the performance of various endpoints, assess inclusion and exclusion criteria and better understand how variations in target patient populations may influence outcomes.  

By pressure-testing design assumptions earlier, sponsors can identify potential limitations, refine protocol decisions and reduce the risk of costly amendments, delays and other downstream challenges before significant operational and financial investments are committed.  

These approaches also offer regulators and investors a more sophisticated narrative, demonstrating that trial design decisions are grounded in robust, data-driven foresight rather than assumptions alone.  

Early, Open Dialogue with Regulators is Essential 

Even the most advanced predictive approaches and RWE strategies cannot substitute for early regulatory alignment. In a one-trial environment, proactive engagement with the FDA becomes essential to ensure that design assumptions, endpoint selection and evidentiary plans are aligned before a pivotal study is underway. 

For sponsors pursuing global development and commercialization strategies, there will be additional complexity because global regulatory expectations vary. While the EMA may accept a single pivotal study in certain circumstances, it continues to apply a science-based, case-by-case approach that requires compelling evidence. In the Asia-Pacific region, there is similarly wide variability in regulatory requirements and evidentiary standards with countries maintaining distinct regulatory frameworks and differing expectations for clinical trial design, data, and approvals.  

As a result, evidence generation strategies must be globally aligned from the outset, balancing FDA flexibility with the broader regulatory and commercial requirements needed to support worldwide approval and market access.  

Strengthening the Evidence Generation Strategy Upstream 

One of the FDA’s rationales for shifting its default position from two to one pivotal trial is the expectation that it will substantially reduce costs while accelerating clinical development, getting new therapies to patients who need them faster. This change places a higher premium on making smarter decisions earlier, before capital, timelines and credibility are fully committed.  

Sponsors that leverage RWE to align trial design with real-world practice, build more representative study populations, strengthen endpoint selection and anticipate regulatory expectations are better positioned to protect their investment and to translate a single successful trial into durable regulatory, commercial and real-world success. 

Contributor

Ashley Brenton, Ph.D. 
Vice President and Global Head, RWE 
[email protected]