Accelerated Approval's Confirmatory Trial Clock Now Starts Before the Approval Letter

The Food and Drug Omnibus Reform Act of 2023 (FDORA) did more to accelerated approval than tighten oversight at the margins. It rewrote FDCA section 506(c) itself — the statute behind every accelerated approval and other expedited pathway decision — to let FDA require that a confirmatory trial be underway before it grants approval, not merely planned, and to give the agency a faster route to withdraw approval when that trial fails or a sponsor doesn't push it forward. Three years on, with FDA's own 2025 draft guidance in hand, the mechanics are settled enough that a VP RA or VP Clinical building an accelerated approval program needs to plan around them from day one — not discover them at the pre-BLA meeting.

What FDORA actually changed in section 506(c)

Before FDORA, section 506(c) let FDA condition accelerated approval on a sponsor's agreement to conduct postapproval studies — a commitment that, in practice, sometimes sat unstarted for years before a trial actually enrolled a patient. FDORA's Section 3210, titled "Modernizing Accelerated Approval," closed that gap directly: FDA may now require, as appropriate, a study or studies to be underway prior to approval, or within a specified time period after the date of approval. The discretion is FDA's — the statute says "may," not "must" — but it converts confirmatory-trial timing from a negotiable expectation into a condition the review division can write into the approval itself.

The confirmatory-trial-underway requirement, in practice

"Underway" is doing real work in the statute, and FDA has not left it undefined. In January 2025, the agency issued draft guidance — Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial Is Underway — laying out the factors it weighs, from protocol finalization and site activation to enrollment progress, when it decides whether a study genuinely qualifies. Because that determination can shape the approval timeline itself, the trial-design conversation now belongs inside the same FDA meeting strategy as the marketing application, not after it: a sponsor that waits to design the confirmatory protocol until after the review division raises it is negotiating from behind.

• If FDA requires a postapproval study, it must specify the conditions of that requirement — enrollment targets, the study protocol, and milestones including a target date for study completion.
• If FDA does not require a postapproval study, it must publish its rationale for that decision, giving sponsors and observers a documented basis rather than a silent exception.
• Either way, the sponsor reports progress every 180 days, beginning 180 days after the date accelerated approval is granted — a recurring regulatory deliverable, not a one-time commitment letter.

The confirmatory trial used to be a promise made at approval. Under FDORA, for many programs it is a condition of approval — and the clock on it can start before the approval letter is even signed. Why the underway requirement changes program planning

Expedited withdrawal: how the clock actually runs

The other half of FDORA's rewrite is what happens when the confirmatory trial doesn't hold up. Section 506(c) now lists specific grounds for expedited withdrawal: the sponsor fails to conduct a required postapproval study with due diligence; a required study fails to verify the predicted clinical benefit; other evidence shows the product has not been shown to be safe or effective under its conditions of use; or the sponsor disseminates false or misleading promotional materials about the product. What changed procedurally is just as consequential as the grounds themselves — FDORA replaced the old notice-and-public-hearing process, which could stretch for years, with an expedited path that still affords the sponsor an opportunity for a meeting with, and a written appeal to, the Commissioner or a designee. FDA's 2025 draft guidance states that the agency will generally convene an advisory committee to weigh in before withdrawal, so the process is faster than before FDORA, not summary.

None of this is unique to a single therapeutic area, but the exposure concentrates where accelerated approval concentrates — heavily in oncology regulatory strategy, where surrogate endpoints and confirmatory overall-survival trials are the norm rather than the exception. The design decisions that used to live entirely inside a Special Protocol Assessment conversation now also have to answer FDORA's underway question: not just whether the confirmatory trial's design is agreed, but whether its timeline can support being underway on FDA's terms. Programs that treat the two conversations as one, rather than sequencing SPA first and FDORA timing later, are the ones that keep the approval and the confirmatory trial moving on the same clock.