The US Food and Drug Administration (FDA) recently reaffirmed that its default standard for the marketing authorisation of novel products is one adequate and well-controlled clinical trial supported by confirmatory evidence.
This announcement has generated significant discussion across the biopharmaceutical industry and raises important strategic considerations for drug development. While some view this as a policy shift, the FDA has held the statutory authority to approve products based on a single pivotal trial, supplemented by confirmatory evidence, since 1997.
An analysis of FDA new drug approvals shows that, since 2020, the majority of new molecular entities have been approved on the basis of a single pivotal trial, with 59% of approvals in 2025 relying on just one pivotal study. While single‑trial approvals remain most common in oncology, they are also increasingly seen in cardiology, haematology, endocrinology, and nephrology.
However, according to the FDA, there remains confusion amongst drug developers about the settings in which a single trial will be accepted.
Building clinical credibility in a single pivotal trial
When a drug development programme relies heavily on a single pivotal trial, the quality and credibility of that trial become critical. Regulatory confidence is strengthened by factors such as:
- The use of an appropriate and contemporary control arm that reflects current standard of care.
- Robust blinding and randomisation procedures.
- Well-justified inclusion and exclusion criteria.
- The appropriate use of run-in periods and concomitant therapies.
- Clinically meaningful primary endpoints.
- A substantial and clinically relevant treatment effect.
- Adequate statistical power and rigorous statistical planning.
- Bayesian or integrated statistical approaches where appropriate.
- Consistency in outcomes between different endpoints.
- Independent review and adjudication processes.
- Transparent and robust handling of missing data.
- Strong biological plausibility, including biomarker evidence and demonstration of target engagement.
- Post-protocol therapies that align with contemporary US practice.
What constitutes confirmatory evidence?
The FDA recognises that evidence extending beyond the pivotal trial may strengthen the overall benefit-risk assessment. Confirmatory evidence could include:
- Data supporting the drug’s mechanism of action.
- Relevant non-clinical evidence.
- Dose-response analyses.
- Clinical data from related indications.
- Evidence generated from other products within the same therapeutic class.
- Real-world evidence.
- Additional adequate and well-controlled clinical trials.
Potential benefits of single pivotal trials
The increased acceptance of single pivotal trial approvals may offer several advantages, including:
- Reducing patient exposure to placebo or inferior therapy.
- Lowering development costs and improving the likelihood of investment.
- Shortening drug development
- Providing earlier patient access to innovative treatments, particularly when used alongside other initiatives to speed drugs to market (including FDA Breakthrough Therapy designation, Accelerated Approval, and Priority Review pathways).
- Lowering drug prices.
- Increasing focus on trial quality because the evidentiary burden rests predominantly on one trial. Weaknesses that might previously have been tolerated across two or more trials may no longer be acceptable.
Potential drug development challenges and risks
Despite these advantages, several concerns remain:
- Some stakeholders may perceive the approach as a lowering of regulatory standards, although the FDA disputes this interpretation.
- A single pivotal trial leaves little room for operational or methodological shortcomings.
- The risk of false-positive findings may increase if evidence is not sufficiently robust.
- Independent replication of results remains scientifically valuable.
A higher bar for a single clinical trial
In practice, a development strategy centred on a single pivotal trial is unlikely to mean lower evidentiary expectations. Rather, sponsors should anticipate that the FDA will expect:
- Larger treatment effects.
- Cleaner and more clinically meaningful endpoints.
- Stronger controls.
- More rigorous statistical methodologies.
- Adequate sample sizes.
- Compelling corroborative evidence.
Health technology assessment bodies and payers may also scrutinise single-trial evidence more closely when making reimbursement decisions following new drug approvals.
When might the FDA require ≥2 pivotal clinical trials for approval?
The FDA may require multiple pivotal trials in circumstances such as:
- Products with non-specific or poorly understood mechanisms of action.
- Interventions relying on highly variable, short-term, or surrogate endpoints.
- Clinical trials that contain significant limitations or methodological concerns.
Implications for drug development
Drug developers considering a single pivotal trial strategy should:
- Review relevant FDA guidance for the specific disease area and product type.
- Engage early and proactively with the FDA about the design of the pivotal clinical trial.
- Establish evidentiary expectations through formal regulatory interactions.
- Avoid assuming that a single trial will automatically be sufficient for approval.
- Consider the clinical trial requirements of other global regulatory bodies if seeking new drug approvals beyond the US.
- Choose the most appropriate regulatory pathways that allow rapid delivery of product to patients.
For further guidance on designing a development programme that supports rapid regulatory approval and generates the evidence needed to secure medical confidence and healthcare payer reimbursement, speak to our experts today.