When One Trial Does the Work of Two: Why Evidentiary Architecture is Critical

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:

• supportive clinical studies

• biomarker or pharmacodynamic data

• dose-response relationships

• natural history datasets

• real world evidence

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 .

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:

• Shorter development timelines

• Lower Phase 3 costs

• Smaller clinical programs
• Faster access to market

In other words, the narrative quickly becomes: one trial instead of two. But regulatory evidence rarely works as a simple numerical substitution.

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.

When a development program relies on a single pivotal trial, the expectations for that trial often increase.

The study typically needs to demonstrate:

• Clear and clinically meaningful treatment effect

• Strong statistical significance

• Consistency across endpoints and patient subgroups
• Rigorous trial design and execution

In many cases, a single pivotal trial must carry more evidentiary weight than either of two traditional confirmatory studies. And importantly, the trial rarely stands alone.

Regulators still evaluate the totality of evidence surrounding the therapy — the clinical data, the biological rationale, the supporting datasets from earlier studies, and the overall coherence of the development program.

The paradigm therefore becomes less about counting trials and more about constructing convincing evidence architecture.

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.

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:

• Manufacturing consistency across clinical lots

• Control of critical quality attributes

• Analytical characterization and potency assays

• Comparability following manufacturing changes
• Bridging between clinical and commercial manufacturing processes

These considerations are especially relevant for cell and gene therapies, where manufacturing complexity is inherently higher, and small process changes can have meaningful product implications.

When clinical replication decreases, the reliability of the product becomes even more important.

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.

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:

• Treatment effects are large

• Biological mechanism is well understood

• Patient populations are small
• Unmet medical need is high

This is why single-trial approvals have historically been more common in areas such as rare genetic diseases, oncology, and certain advanced therapies. In these contexts, a well-designed pivotal trial combined with strong supporting evidence can provide sufficient confidence for regulatory decision-making.

Ultimately, the FDA’s recent discussion of single pivotal trials should not be interpreted as a relaxation of evidentiary standards. If anything, it reflects a shift in how evidence is assembled and evaluated.

The pivotal trial remains central. But it increasingly serves as the anchor within a broader framework of clinical, mechanistic, and manufacturing evidence. When one trial must do the work of two, the overall evidentiary architecture becomes even more important. And when clinical replication decreases, confidence must come from somewhere else.

That confidence will come from stronger trial design, integrated evidence packages, and manufacturing processes capable of delivering consistent product quality. In that sense, the emerging single pivotal trial paradigm is not really a shortcut. It is simply a different way of constructing proof.

Please do not hesitate to connect. We are ready when you are, capable of advising on your questions and challenges as you consider moving to a single pivotal trial approach in the U.S.