What Accelerated Approval’s Confirmatory Trial Requires

Accelerated approval has always been a conditional bargain: FDA lets a sponsor market a drug on the strength of a surrogate or intermediate clinical endpoint reasonably likely to predict clinical benefit, and the sponsor owes a confirmatory trial to verify that the benefit is real. For most of the pathway’s history, what happened when a sponsor didn’t deliver that trial — or delivered one that failed to confirm benefit — was the weakest part of the deal. The Consolidated Appropriations Act of 2023, through its FDA-specific title known as FDORA, rewrote that part of the bargain in December 2022, and anyone reading an accelerated approval today needs to read it against the current rules, not the ones that applied before.

In brief

Accelerated approval under FD&C Act section 506(c) (21 U.S.C. § 356(c)) lets FDA approve a drug for a serious condition on a surrogate or intermediate clinical endpoint reasonably likely to predict clinical benefit, conditioned on a confirmatory trial to verify that benefit.
FDORA, enacted December 2022, rewrote section 506(c) to let FDA require the confirmatory trial be underway before approval or shortly after, and to specify conditions — such as enrollment milestones — the trial has to meet.
Failing to pursue a required postapproval study with due diligence, including the specific conditions FDA set, is now an explicit statutory ground for withdrawal — and a prohibited act in its own right.
Withdrawal now runs through an expedited procedure: notice with an explanation, an opportunity to meet with the Commissioner or a designee, a written appeal, public comment, and an advisory committee only if one is requested and none has already advised on the same questions.
The approval standard itself didn’t change. What changed is how quickly FDA can act once the trial a sponsor promised doesn’t happen, or doesn’t confirm the benefit the surrogate endpoint predicted.

Why the confirmatory trial was always the weak link

Congress gave the accelerated approval pathway explicit statutory footing in section 506(c) of the FD&C Act through the FDA Safety and Innovation Act of 2012, building on a mechanism FDA had already been using under its own regulations since 1992. The idea was straightforward: for a serious condition with an unmet need, waiting for a full clinical-outcomes trial before approving anything can cost patients time they don’t have, so FDA could approve on a surrogate endpoint — a lab value or imaging result reasonably likely to predict real clinical benefit — while the sponsor ran a confirmatory trial to check that the prediction held. The part that didn’t get the same statutory attention for years was what happened when a sponsor was slow to start that trial, slow to finish it, or produced one that didn’t confirm the benefit. Withdrawing an approval required a process built around an informal hearing, and in practice it moved slowly enough that a drug could stay on the market for years after its confirmatory trial had failed or simply hadn’t been run.

What FDORA actually changed in the statute

The December 2022 amendments gave FDA tools it didn’t clearly have before. The agency can now require that a confirmatory trial be underway at the time of approval, or specify that it start within a set period afterward, and it can attach conditions to that requirement — enrollment targets, interim milestones, a specific trial design — under the statute’s own terms. A sponsor who doesn’t pursue the required study “with due diligence,” including with respect to whatever conditions FDA specified, is now squarely within the statute’s grounds for withdrawal. That failure is also, separately, a prohibited act under the FD&C Act, which gives FDA a second lever beyond withdrawal itself.

How the expedited withdrawal procedure actually works

The old process tied withdrawal to regulations that had to build in an informal public hearing, which is part of why it moved so slowly. FDORA replaced that with specific statutory steps: FDA gives notice and an explanation of its reasoning, the sponsor gets an opportunity to meet with the Commissioner or a designee, a written appeal, and a public comment period, and an advisory committee is convened only if one is requested and none has already advised on the same questions. That last condition matters — a sponsor who already had an advisory committee weigh in when the approval was granted, or earlier in the withdrawal process, doesn’t automatically get a second one. Reading FDA’s stated basis for a withdrawal action closely is worth the same discipline practitioners already bring to reading a complete response letter — both are FDA explaining, in writing, why it isn’t satisfied, and both reward reading the actual reasoning rather than someone’s paraphrase of it.

Where people get this wrong

Assuming a disappointing confirmatory trial triggers automatic withdrawal

The statute's withdrawal grounds turn on specific findings — a trial failing to verify clinical benefit, or a sponsor's failure to pursue it with due diligence — not on a trial simply missing its topline endpoint before FDA and the sponsor have worked through what that means.

Treating "due diligence" as a generic, unwritten standard

FDA can specify the actual conditions a trial has to meet — enrollment pace, design, timing — and due diligence is measured against those specific conditions, not a vague sense of good-faith effort.

Assuming the expedited procedure means no process at all

Notice, an explanation, a meeting opportunity, a written appeal, and public comment are all still required — what changed is that a full hearing and an advisory committee are no longer automatic.

None of this makes accelerated approval a less useful pathway — it makes the back half of the bargain enforceable in a way it wasn’t before. FDA's own draft guidance on how it will apply these provisions, circulated for comment in late 2024, is worth reading directly rather than through a secondary summary, the same way any FDA guidance document rewards reading the actual text over someone else's paraphrase of it.

Sources & further reading

U.S. Code — 21 U.S.C. § 356(c), Expedited Approval of Drugs for Serious or Life-Threatening Diseases or Conditions law.cornell.edu
FDA — Accelerated Approval Program fda.gov
Regulatory Academy — How to Read an FDA Complete Response Letter regulatoryacademy.com
Regulatory Academy — How to Read an FDA Guidance Document regulatoryacademy.com

This essay is provided for general educational purposes and reflects the regulatory landscape as of its publication date. It is not legal, regulatory, or career advice.