Background

The U.S. Food and Drug Administration (FDA) has long used 'two pivotal trials' as the standard for verifying the efficacy of new drugs. This has served as a key regulatory mechanism to minimize statistical random errors and ensure reproducibility. However, as the cost of new drug development soars and there is growing social demand to expedite patient access to treatments, there is a growing movement to break away from this traditional regulatory framework.

In February 2026, Vinay Prasad, MD, and Marty Makary, MD, proposed in an opinion piece published in the New England Journal of Medicine (NEJM) that 'a single pivotal trial and confirmatory evidence' be established as the new standard for new drug approval. They argued that this would be a practical alternative to reduce the enormous costs associated with additional clinical trials and lower drug prices. This proposal sparked a debate about regulatory flexibility across academia and the pharmaceutical industry.

Key Findings

The letter published in the NEJM on July 9 directly questions the movement toward single clinical trial standardization. The authors argue that the transition to a single clinical trial system is overly focused on theoretical concepts and lacks the essential empirical data needed for decision-making. The most important question that should be addressed in the field of regulatory science is: what is the proportion of cases in which the results of two pivotal trials conducted for the same drug differ?

According to critics, if cases in which the results of the two clinical trials differ are actually frequent, approving new drugs based on a single trial could lead to the introduction of ineffective or even dangerous treatments to the market. Conversely, if the proportion of inconsistent results is negligible, the validity of single clinical trial standardization would be empirically demonstrated. However, neither regulatory authorities nor proponents have provided specific data to answer this question.

There are many examples in the history of clinical trials that demonstrate that these concerns are not unfounded. An analysis of anticancer drug clinical trials conducted by the FDA in the past showed that in more than half of the cases, positive efficacy signals observed in the early stages were not reproduced in the final pivotal trials. Of the 22 cases analyzed, 14 failed to demonstrate efficacy, and in 7 cases, the results were completely reversed due to safety concerns. This clearly demonstrates the value of a second clinical trial as a safeguard to filter out statistical uncertainty.

Significance and Prospects

The proposal for single clinical trial standardization is clearly intended to alleviate the cost barriers to new drug development and provide patients with faster access to treatment options. However, the argument that hasty relaxation without verifying the reproducibility of clinical data could put patients at risk is gaining traction. Ultimately, the key challenge for regulatory authorities in the future will be to determine how to strike a balance between regulatory flexibility and maintaining safety.

Experts suggest that the FDA should disclose its decades of new drug approval and clinical data to academia for independent meta-analysis. In addition, efforts should be made to clearly define the scope of confirmatory evidence proposed to supplement the single clinical trial. Real-World Evidence (RWE) or biomarkers based on mechanisms of action cannot perfectly replace the rigorous statistical verification of clinical trials. If a verification process based on scientific data is not established, breaking away from the established rule of two clinical trials could lead to a loss of trust rather than regulatory flexibility.