From "Two-Trial Dogma" to the Single Pivotal Standard: The Evolution of FDA Evidence Requirements

The "two-trial" rule was born from the 1962 Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act, which mandated that manufacturers prove a drug was not just safe, but also effective. This established the "substantial evidence" standard, which the FDA historically interpreted as requiring at least two adequate and well-controlled clinical trials. This "two-trial dogma" served as a statistical insurance policy: in a world where biologic understanding was more limited, requiring a developer to be "lucky twice" reduced the probability of a false-positive result from 250 in 10,000 to just 6 in 10,000.

However, as of 2026, the regulatory landscape has reached a historic turning point. Here is how the "substantial evidence" requirement evolved from a rigid duplication rule into a flexible, precision-based standard.

1. The 1998 Foundation: Establishing Statutory Flexibility

The first major shift toward modern flexibility arrived with the 1998 Guidance: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. Following the FDA Modernization Act (FDAMA) of 1997, the agency gained formal statutory authority to grant marketing authorization based on a single adequate and well-controlled study combined with "confirmatory evidence".

While this allowed for disease-by-disease flexibility—particularly in oncology and rare diseases, where single trials began to support the majority of approvals—manufacturers remained confused about exactly when a single trial would be accepted. For most "Main Street" drugs or drugs for common diseases, the two-trial expectation remained the functional default.

2. The 2023 Expansion: Defining "Confirmatory Evidence"

In September 2023, the FDA released updated draft guidance "Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence" to clarify what constitutes "confirmatory evidence" when only one pivotal trial is conducted. This guidance acknowledged that modern drug development relies on both statistical and biologic inferences. Under this framework, a single trial could be bolstered by:

• Clinical Evidence from a Related Indication

• Mechanistic or Pharmacodynamic Evidence

• Evidence from Relevant Animal Model

• Evidence from Other Members of the Same Pharmacological Class

• Natural History Evidence

• Real-World Data/Evidence (RWD/RWE)

• Evidence from Expanded Access Use of an Investigational Drug

3. The 2026 Paradigm Shift: The New Default

Last week, in February 2026, the FDA officially ended the "two-trial dogma." In a landmark article "One Pivotal Trial, the New Default Option for FDA Approval - Ending the Two-Trial Dogma" in the New England Journal of Medicine, FDA officials announced that a one-trial requirement is now the agency's new default standard for drug approval. We are waiting for the formal FDA guidance to provide the details about this paradigm shift.

Why the shift?

• Precision and Biology: Modern drug discovery is increasingly precise. The FDA now considers biochemical changes and biomarkers that tell a "complete biologic story," making overreliance on a second trial unnecessary when the "mechanistic science is sound".

• Economic Relief: A single pivotal study can cost between $30 million and $150 million and take years to complete. By moving to a one-trial default, the FDA aims to lower capital costs and remove a primary justification for high drug prices.

• Quality Over Quantity: Officials argue that two trials can provide "false assurance" if their designs are deficient (e.g., substandard control arms or dubious endpoints). The agency will now focus its energy on ensuring the single required trial is "robust and sound".

The Guardrails: When Two Trials Are Still Required

The FDA will not abandon the two-trial standard entirely. Additional studies may still be required if:

• An intervention has a nebulous or nonspecific mechanism of action.

• The trial affects only a labile or short-term surrogate outcome.

• The primary trial has underlying limitations or deficiencies.

Conclusion

We have moved from an era of Replication (the 1962-1998 standard) to Precision (the 2026 default). By formally changing the "default option," the FDA expects to spur a surge in biomedical innovation and speed life-saving drugs to the patients.

Additional Reading:

• raps.org Experts react to FDA’s shift to single pivotal trials for most drugs
• fda.gov (2016) Promoting Safety and Effective Drugs for 100 years
• Sasinowski et al (2012) Quantum of Effectiveness EVidence in FDA's Approval of Orphan Drugs
• Sasinowski et al (2015) Quantum of Effectiveness Evidence in FDA's Approval of Orphan Drugs: Update, July 2010 to June 2014