Phase 4 Trial

A Phase 4 trial is a clinical study conducted after a drug has received FDA marketing approval, commonly called a post-marketing or post-approval study. It is not one of the phases 21 CFR 312.21 formally defines — that regulation covers only pre-approval testing under an active IND. Phase 4's regulatory basis instead comes from the FDA Amendments Act of 2007, which added 21 U.S.C. section 355(o) to the FD&C Act, authorizing FDA to require postmarketing requirements (PMRs, mandatory and enforceable) as distinct from postmarketing commitments (PMCs, voluntary but reported annually under section 506B) and from studies required under a Risk Evaluation and Mitigation Strategy (REMS) at section 355-1. Phase 4 studies typically enroll thousands of participants and can run indefinitely to detect rare, long-term, or subpopulation-specific effects.

ByCASRAI Editorial Board

· Last updated 25 Aug 2026

Required (PMR) vs. voluntary (PMC) vs. purely elective

Not every Phase 4 study is mandatory. FDA distinguishes postmarketing requirements (PMRs) — studies or trials a sponsor is legally required to conduct under § 355(o) or another statute/regulation, with FDA enforcement authority if they’re not completed on schedule — from postmarketing commitments (PMCs), which a sponsor agrees to conduct but that aren’t required by statute or regulation, and which sponsors must nonetheless report on annually under FD&C Act § 506B. A separate category of Phase 4 study is neither: sponsor-initiated marketing-support trials, investigator-initiated studies, or registry-based observational work undertaken with no PMR/PMC obligation attached at all. All three are colloquially “Phase 4,” but only the first carries statutory teeth.

REMS-required studies

A related but distinct mechanism is the Risk Evaluation and Mitigation Strategy (REMS), authorized by the same FDAAA 2007 legislation at 21 U.S.C. § 355-1. When FDA approves a drug with a REMS that includes a required assessment or study, that study is a Phase 4 obligation tied to the REMS rather than to a standalone PMR — the distinction matters for how it’s tracked and what happens if it’s missed, but the underlying trial still looks like any other Phase 4 study.

What Phase 4 studies are actually for

FDA’s patient-facing guidance describes Phase 4 as typically enrolling several thousand participants with the disease or condition, with a purpose spanning both “safety and efficacy.” Because Phase 4 studies run in the general treated population — not the more tightly selected population of a pivotal Phase 3 trial — and can run indefinitely rather than for a fixed pre-specified duration, they’re positioned to detect rare adverse events, long-term safety signals, drug-drug interactions, and effectiveness in subpopulations that a pre-approval program was never large or long enough to characterize.

Administrative and regulatory context

Phase 4 sits alongside CASRAI’s Late-Phase Clinical Study term, which covers the broader Phase IIIb/Phase IV industry convention; ongoing drug safety data from Phase 4 and other post-market sources factors into reporting obligations like 21 CFR 314.80 (postmarketing adverse drug experience reporting). See CASRAI’s Clinical Trial Phases guide for how Phase 4 fits alongside Phase 0, Phase 1, Phase 2, and Phase 3.

Use in your systems

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