Regulatory Landscape

Single pivotal trial and confirmatory evidence

The revised draft guidance sets out conditions under which a single adequate and well-controlled investigation, supported by confirmatory evidence, may establish effectiveness. It recommends that sponsors bring both the proposed pivotal design and the confirmatory evidence package to the end-of-Phase-2 meeting.

Project Optimus

Project Optimus reformed dose selection in oncology, moving away from maximum tolerated dose toward a dosage supported by efficacy, safety and tolerability evidence. The final guidance emphasizes evaluating multiple doses early, often through randomized dosage comparison, with PK/PD, biomarker and patient-reported outcome data supporting the rationale. FDA defines dosage as dose and schedule.

Adoption has been uneven. A study of 367 industry-sponsored Phase 1 oncology trials found Bayesian dose-finding design use rose from 48% in 2021 to 75% in 2024, while dose-optimization plans appeared in 30% of protocols and patient-reported outcomes in 12%.

Bayesian methodology in clinical trials

Issued jointly by CDER and CBER, the draft guidance focuses primarily on the use of Bayesian methods to support primary inference in pivotal trials. Among the other applications it describes: governing the timing and adaptation rules for interim analyses in adaptive designs, and informing design elements such as dose selection for subsequent trials. It applies across INDs, NDAs, BLAs and supplemental applications.

Real-Time Clinical Trials

FDA announced two proof-of-concept trials reporting pre-agreed endpoints and safety signals to the agency as data accumulates, alongside a Request for Information for a broader pilot program. In the RFI, the agency describes early-phase development as a bottleneck marked by high uncertainty, limited patient populations and inefficient decision-making. A stated objective is supporting “continuous trials,” in which transitions between traditional phases are streamlined or eliminated.

Operation TrialBlazer

A coordinated federal effort to accelerate early-phase clinical development in the United States and reverse the movement of early trials offshore. Among its targets is protocol complexity: HHS estimates that upstream protocol simplification could reduce development cost by up to 22%. Supporting analysis cites Tufts CSDD research finding roughly 45% of protocol amendments are avoidable.

M15: general principles for model-informed drug development

ICH adopted the M15 guideline at Step 4 on 29 January 2026. FDA announced availability of the corresponding final guidance in the Federal Register on 3 June 2026, finalizing the draft issued in December 2024 under docket FDA-2024-D-5580. The guideline gives general recommendations for planning model-informed work, evaluating models and their outcomes, and documenting the resulting evidence. It also sets out a harmonized framework and shared terminology for assessing that evidence, including an assessment table for use in regulatory interactions.

FDA recommends that sponsors use the guidance when preparing requests and packages for the Model-Informed Drug Development Paired Meeting Program.

Master protocols for drug and biological product development

FDA issued a revised draft guidance on 22 June 2026, replacing the December 2023 draft and incorporating stakeholder comments received on it. The revision adds a section on basket trials and retains coverage of umbrella and platform designs. FDA noted that the revision responds to requirements in the Food and Drug Omnibus Reform Act of 2022 concerning clarity on streamlining trial logistics and on collecting and analyzing data efficiently.

Among the design and analysis topics addressed: whether the primary objective is the average effect across a combined population or the effect within each individual disease, condition or subtype; allocation to shared control arms; changes to randomization ratios as products enter and exit a platform trial; and the use of concurrent and nonconcurrent controls, where participant characteristics, trial conduct and standard of care may shift over the duration of the trial.