The U.S. Food and Drug Administration's (FDA) recent discussion of a single pivotal trial approach has generated excitement across the biotechnology sector. At first glance, the concept sounds simple and appealing. If one well-designed study can support approval, development programs could potentially move faster, require fewer patients, and consume less capital.
But as with many things in drug development, the regulatory reality is more nuanced.
When clinical replication decreases, confidence must come from somewhere else. And increasingly that confidence will come from stronger trial design, integrated evidence packages, and more robust manufacturing control.
To understand why, it helps to step back and look at how the current evidentiary standard emerged in the first place, unpack single pivotal trial expectations, and review key risks and recommendations so sponsors can prepare.
Our experts Monika Swietlicka, Principal Consultant Regulatory Affairs and Mike Fusakio, Senior Consultant Regulatory Affairs will answer some important and clarifying questions.
Monika: The modern framework for drug approval in the U.S. traces back to the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act. Those amendments established the requirement that sponsors demonstrate "substantial evidence of effectiveness" before a drug can be approved. Importantly, the statute does not explicitly require two clinical trials. Instead, it defines substantial evidence as evidence derived from adequate and well-controlled investigations conducted by qualified experts. However, over time, regulatory practice evolved to interpret this standard as typically requiring two adequate and well-controlled studies demonstrating consistent results. The logic was straightforward - replication across independent trials reduces the chance an observed treatment effect is simply a statistical anomaly or study-specific bias. By the late twentieth century, the two-trial paradigm had become deeply embedded in how development programs were designed. But even then, the law always allowed flexibility. In the late 1990s, the Food and Drug Administration Modernization Act (FDAMA) clarified that substantial evidence could, in some circumstances, be demonstrated through one adequate and well-controlled clinical investigation supported by confirmatory evidence. That confirmatory evidence might come from several places, including:
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| Mike: The FDA's recent shift and focus on a single pivotal trial for registration is framed as an opportunity to reduce product development burdens, including cost and time. A key focus of the current administration. These changes are happening in step with the industry - a continuation of a global trend, with new regions becoming development hot spots. The rules themselves are not changing, rather, there's a strong focus on regulatory flexibility that was actually there to begin with. While flexibility has always been present, its implementation is now more front and center, resulting in an evolving field of product development, which introduces significant risks and opportunities for sponsors. FDA's pivot from two trials to one can be viewed as a potential opportunity, by reducing the potential investment required to bring a product to market. However, sponsors must evaluate whether this change from the FDA will actually reduce . | |
Monika: Unsurprisingly, the biotech ecosystem is interpreting this as a potential shift toward simpler development programs. The expectations are easy to understand. Sponsors and investors see the possibility of:
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| Mike: Sponsors now must evaluate the use of a single trial in a global development setting, CMC and nonclinical development timelines, and the FDA itself. There are now more components to consider when looking to launch just one trial, particularly in a global setting. The introduction of Real-World Evidence, adaptive designs, and other practices has allowed trials to collect and assess more data resulting in potentially a more effective means of evaluating the objectives of any one study. However, as a by-product, these studies have become significantly more complex, requiring significantly more input and discussion to align an approach. Alignment that must be achieved to ensure the acceptability of the data for approval. These discussions become more complicated when incorporating additional global regulatory authorities. Sponsors must consider the timing and impact of having to discuss, align, and amend protocols across multiple regions, such as the U.S, Europe, and China. | |
Monika: When a development program relies on a single pivotal trial, the expectations for that trial often increase. The study typically needs to demonstrate:
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| Mike: As we've both noted, the FDA has made it clear that expectations for approval are still the same, which means that even with recent efforts by the FDA to speed up CMC and nonclinical development, these timelines must still align with clinical development. Sponsors must ensure that the focus on the potentially reduced timelines for clinical development does not leave them behind in preparing the necessary data and content for CMC and nonclinical packages. Additionally, a key question remains - how will this shift in product development move forward? The current thinking from the FDA is based on the previously noted article by Dr. Makary and Dr. Prasad. With Dr. Makary and Dr. Prasad's departure from the FDA, will the new FDA Commissioner and the new CDER and CBER directors champion this cause to the same extent? As this proposed change is not in the CFR, sponsors must also consider whether this will be the FDA's thinking by the end of this administration. This proposed change is framed by the FDA as a major shift from the Agency, but there is limited guidance on how it will be implemented, which leaves sponsors in a position of risk. | |
Monika: I agree completely. One aspect of the single-trial paradigm that receives far less attention is its potential impact on manufacturing and CMC expectations. When two independent pivotal trials are conducted, some degree of variability in manufacturing processes or clinical supply lots can be absorbed across multiple datasets. Replication of clinical findings across trials provides confidence that the treatment effect is robust despite small variations in product quality attributes. In a development program built around a single pivotal trial, redundancy disappears. Suddenly, the clinical evidence supporting effectiveness originates from one dataset generated with a specific manufacturing process and a defined set of clinical supply lots. As a result, regulators may place greater emphasis on demonstrating manufacturing robustness and product consistency. This can translate into increased scrutiny of:
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| Mike: The best approach for sponsors is to continue with current best practices from a regulatory perspective, including frequent and well thought through discussions with the Agency. These frequent alignment discussions will keep sponsor companies as aligned as possible with the Agency, even if (and when) their thinking evolves. | |
Monika: None of these changes, ramifications, or implications means the single pivotal trial model will not work. In fact, there are many settings where it is entirely appropriate. The approach tends to work best when:
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