For the first time, FDA explains how it plans

to implement a critical process for

accelerated approval reforms
In December 2022, the FDA received important new authority allowing it to require, “as
appropriate,” that a confirmatory study or studies be underway before it would grant accelerated
approval to a drug product or biologic. Now, in a long-awaited draft guidance document, the FDA
has for the first time described the criteria sponsors must meet to demonstrate that the study is
“underway,” including granular plans and enrollment of participants.

BY AMANDA CONTI JAN 6, 2025 8:10 PM EST

Background: What is Accelerated Approval,

and how has it recently changed?
Accelerated approval is a regulatory mechanism by which certain drugs intended to
treat serious or life-threatening conditions with unmet medical needs can be approved
more quickly. Unlike traditional approvals, the FDA allows a company to make use of so-
called “surrogate” or “intermediate” endpoints. These endpoints are intended to be indicative
of a benefit to patients, such as the shrinkage of a tumor (the surrogate endpoint) indicating a
likelihood of a response that would result in longer overall survival of the patient (the
traditional endpoint). Or, to quote the program’s authorizing statute, the surrogate or
intermediate must be considered “reasonably likely to predict the clinical benefit of that drug.”
However, because the endpoints used to support accelerated approval are only
indicative of a benefit to patients, the FDA wants to confirm that the product is as safe
and effective as was hoped. To assure this, FDA requires that companies conduct post-
approval studies (also known as Postmarketing Requirements, or PMRs) to confirm the
benefit of their products. These PMRs are generally agreed upon at the time of the approval.
Successful completion of the confirmatory studies results in conversion of the accelerated
approval to a traditional approval. If the studies fail to demonstrate a benefit, then FDA may
withdraw the drug from the market.
Confirmatory studies can be challenging to conduct, and some companies may fail to
complete them on time – or at all. For example, companies may find it difficult to fully enroll
a clinical trial after their drug is approved, since there is little incentive for patients to enroll in
a study if they can just obtain the product by other means. As a result, many PMRs are
behind schedule, and products with unconfirmed clinical benefit can linger on the market for
years. These are so-called “dangling” accelerated approvals have been under FDA’s
microscope in recent years.

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 FDA historically lacked the ability to compel companies to act in these cases without
undertaking significant effort. Though the FDA Amendments Act of 2007 gave FDA
authority to mandate PMRs and levy limited fines on companies that do not meet their
obligations, these are not especially steep – just $250,000 per violation, and not more than
$1 million for all prior violations. In instances when FDA did wish to withdraw a drug from the
market with a failed confirmatory study, the FDA needed to undergo a lengthy and onerous
process. As a result, FDA typically worked behind the scenes to ask, pleased or cajole
companies to withdraw their products from the market.

In response to these issues, Congress gave

FDA several new authorities related to
accelerated approval in late 2022.
The Food and Drug Omnibus Reform Act (FDORA), passed as part of the FY 2023
federal budget bill (the Consolidated Appropriations Act, 2023), contained a spate of
new requirements and authorities for granting accelerated approval.
Confirmatory studies underway: FDA can require, “as appropriate,” that a study or studies
be underway prior to approval, or within a specified time period after the date of approval” for
a product granted accelerated approval.” FDA has already begun to require this for certain
companies as a condition of approval, but Congress has now granted FDA the explicit
authority to do so. FDA’s Oncology Center of Excellence (OCE) in March 2023 guidance that
confirmed that such confirmatory studies should either be “fully accrued and well underway”
or “well underway, if not fully enrolled” at the time of approval. Then, in late March 2024, the
OCE issued two Complete Response Letters to Regeneron citing this authority. [Read
AgencyIQ’s analysis of these CRLs here.] As AgencyIQ has previously discussed, this does
not mean the agency must require this, which was made clear in CBER’s February 2024
Standard Operating Policies and Procedures (SOPP) document on procedures for
developing postmarketing requirements and commitments, indicating that some flexibility
may be warranted.
Speedier withdrawals: FDA gained the ability to expedite the process of withdrawing
accelerated approvals. The new statutory requirements echoed some aspects of existing
processes (i.e., give a sponsor due notice, provide an explanation for the proposed
withdrawal, and offer an opportunity for a meeting and a written appeals process, permit
public input, and allow input from an advisory committee). However, it would be able to act
more quickly if a sponsor failed to act on the “conditions specified by the Secretary.” FDA has
already used this authority to modestly accelerate the removal of one product.
Higher penalty potentials: For active, ongoing violations, FDA can levy penalties of up
$250,000 for the first month of the violation, and then $1 million per month thereafter, up to a
maximum of $10 million. However, this authority seems to have been largely neutered
following a subsequent Supreme Court case, SEC v. Jarksey, which found that civil
monetary penalties could only be imposed by courts – not by the FDA.
Regular reports: Companies can be required to send updates to the FDA every 180 days
on the status of the PMRs, including progress toward enrollment targets, milestones and
other information required by the FDA. There’s also a requirement for the FDA to “promptly”
post this information publicly, which could be a boon to researchers (and other companies).

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 As AgencyIQ has noted, we’ve already seen FDA modify the language in recent accelerated
approval letters to include reminders about the new FDORA reporting requirements and
deadlines.
PMR assignment accountability: FDORA mandates that if the FDA does not require a
PMR for a drug granted accelerated approval (as is the standard), that it publishes (on its
website) a “rationale for why such study is not appropriate or necessary.” However, the
legislation does not indicate when this publication should occur.
Detailed PMR conditions: FDA is now required to specify the conditions for a post-approval
study (or studies), “which may include enrollment targets, the study protocol, and milestones,
including the target date of study completion.” Previously, FDA generally only published
information about the high-level requirements of the required study.
New guidance: The law directed FDA to develop guidance within 18 months of its passage—
i.e., by the end of June 2024—to describe: 1) “How sponsor questions related to the
identification of novel surrogate or intermediate clinical endpoints may be addressed in early-
stage development meetings,” 2) the use of “novel clinical trial designs” to complete
confirmatory studies, 3) the new procedures by which FDA can withdrawal accelerated
approvals per FDORA, and 4) any further considerations in “evaluating the evidence” on the
use of novel surrogate or intermediate clinical endpoints.

FDA recently published guidance documents

with its interpretation of these reforms – in
part.
In early December 2024, FDA published a draft procedural guidance interpreting
some—but not all—of these FDORA reforms. The document addressed two topics: (1)
granting and (2) withdrawal of accelerated approval.
However, FDA mostly steered clear of the question of how to determine if studies are
adequately underway at the time of approval. FDA did state in the guidance that
confirmatory studies should generally be underway at time of application submission.
Further, the document explains that “Except in limited circumstances, FDA intends to require
that confirmatory trial(s) be underway prior to granting accelerated approval.” [Read full
AgencyIQ analysis here.].

Now, FDA has issued a complementary new

procedural draft guidance that expands on
the meaning of “underway.”
Released on Jan. 6, 2025, the draft guidance document is just seven pages in length.
In the introduction, the agency walks through the risks associated with accelerated approval.
These include exposure to a drug that ultimately does not demonstrate clinical benefit or to
adverse events that were not identified in a smaller or shorter study.

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 Per the draft, “It is critical that such studies are promptly initiated and completed in a
timely manner to limit the time that a drug is approved for an indication without verification
of clinical benefit.” The agency emphasizes that this is “especially important” for drugs
associated with “considerable toxicity.”

FDA describes its intention for confirmatory

trials to be underway prior to an accelerated
approval action.
The guidance aligns with the ethos that conversations about verifying the benefit of
an accelerated approval product should be shifted earlier in the development process.
The confirmatory trial design should be developed and signed off on prior to the initial
application submission. Specifically, the guidance instructs sponsors to request a meeting
with the agency “soon after sponsors and FDA reach preliminary alignment that a
development program could support accelerated approval.” This big-picture meeting should
address the “comprehensive drug development program,” which includes the confirmatory
trial. The sponsor and FDA should reach agreement on the design following the agency’s
review of draft protocols, which should occur “as soon as practicable, and generally soon
after the End-of-Phase 2 meeting.”
In line with the new authorities, FDA “generally intends to require that the confirmatory trial
(s) be underway prior to the accelerated approval action.” The exceptions are expected to be
very limited, with the document providing the example of “an infectious disease outbreak that
has not yet occurred.”
Defining “underway”: FDA outlines three new, general criteria: “(1) the trial has a target
completion date that is consistent with diligent and timely conduct of the trial, considering
the nature of the trial’s design and objectives, (2) the sponsor’s progress and plans for
postapproval conduct of the trial provide sufficient assurance to expect timely completion of
the trial, and (3) enrollment of the confirmatory trial has been initiated.”
FDA walks through the setting of the proposed target completion date, which should
be accompanied by a “clear and sound justification.” This justification should incorporate
information on the natural history of the disease, the availability of alternative treatments
(“before and after accelerated approval”), and recruitment history and anticipated challenges.
The date should also incorporate time for the efficacy analyses and any associated follow-
ups.
When assessing progress and plans, FDA considers accrual rates and other metrics,
as well as the pace of site activation. As part of the planning process, sponsors are
expected to propose measurable benchmarks (“e.g., participant recruitment goal, extent of
site activation, proportion of primary endpoint events accrued”) for the confirmatory trial that
support the target completion date. Importantly, the guidance states that “Sponsors should
discuss with FDA whether the proposed benchmark(s) is/are acceptable prior to submission
of the application.” Delays in meeting “one or more” benchmarks may impact the agency’s
accelerated approval decision.
FDA will expect enrollment to be complete prior to approval for some studies: Initiated
enrollment seems to be the minimum status for the trial to be considered underway. For
confirmatory trials expected to have challenging enrollment or retention (i.e., studies in the
same indication rather than a similar one), the agency states that it may require enrollment to
be complete at the time of accelerated approval.

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 Confirmatory trials should focus first on the U.S., according to the concluding
sentence of the document. The agency advises: “[T]o ensure the confirmatory trial enrolls
and retains sufficient U.S. participants, the sponsor’s enrollment strategy should prioritize
early U.S. recruitment, and U.S. recruitment should be closer to completion at the time of
accelerated approval.” This is particularly interesting given the agency’s recent
encouragement of the use of multiregional clinical trials (MRCTs) [Read AgencyIQ’s analysis
of OCE’s Sept. 2024 guidance here].
Rare disease considerations are woven throughout the document. FDA may not require
confirmatory studies to be underway for certain rare diseases with “very small populations
with high unmet need” with appropriate justification. However, this is not a blanket exclusion.
The guidance discusses strategies to enable postmarketing studies for rare diseases, like
nonrandomized designs. The agency also acknowledged that many rare disease
development programs rely on a prespecified interim analysis of a surrogate or intermediate
clinical endpoint to support accelerated approval during an ongoing trial. “Such a trial would
be considered underway as long as the trial is expected to complete in a timely manner,”
says the guidance.

Analysis
The guidance makes clear that FDA wants fully fleshed out confirmatory study plans
prior to application submission—and enrollment prior to action on that submission.
This clears up a bit of confusion surrounding the order of operations. In March 2023, OCE
published its thinking on Clinical Trial Considerations to Support Accelerated Approval of
Oncology Therapeutics [See AgencyIQ analysis here.] That guidance states that not only
should confirmatory studies for drugs seeking accelerated approval be “underway” at the
time of approval, but potentially “well underway, if not fully enrolled.” In addition, the
confirmatory trial should be “underway when the marketing application is submitted,” FDA
wrote. The new guidance puts clearer operational meaning behind these terms.
While FDORA’s language gives FDA authorities to specify confirmatory trial
requirements, the guidance indicates that this will likely be a more collaborative
process. The onus is placed on the sponsor to request meetings, draft protocols, and
propose the target completion date and benchmarks. While this will increase administrative
burden and upfront investment on the part of sponsors, the agency appears willing to
consider the sponsor’s justifications, though it remains to be seen how closely the agency will
align with these proposals in the PMRs issued at approval.
As AgencyIQ wrote regarding the previously discussed Dec. 2024 guidance on
expedited withdrawals, this document should be read as being part of FDA’s
ecosystem of accelerated approval guidance. The agency’s foundational guidance on
accelerated approval and other expedited programs was published in May 2014. FDA has
subsequently released multiple product-class specific guidance documents related to
accelerated approval. In addition to the March 2023 guidance, the agency has laid out its
expectations for specific indications, like its 2020 guidance on accelerated approvals in early-
stage breast cancer [See AgencyIQ analysis here.].
More guidance is expected to come from FDA in the coming year. As explained in a
footnote, “FDA intends to address in other guidance complementary authorities added by the
Consolidated Appropriations Act, 2023 to help ensure timely study completion.” The agency
has yet to address how sponsors can submit 180-day progress reports on the confirmatory
trials. In addition, AgencyIQ notes that the just-released Center for Biologics Evaluation and
Research (CBER) 2025 Guidance Agenda has carried over a draft guidance entitled

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 "Accelerated Approval of Human Gene Therapy Products for Rare Diseases” from the
previous year [Read full AgencyIQ analysis of the agenda here.].
This comes as the stakes for accelerated approval products could heighten.
Historically, payers have viewed products approved via accelerated approval similarly to
those approved under the traditional pathway. Recently, a new policy from Pennsylvania-
based health insurer Independence Blue Cross would consider non-oncology drugs,
biologics or gene therapies granted accelerated approval “a benefit contract exclusion for
most plans,” and therefore exclude it from reimbursement for 18 months. Should this policy
become adopted more broadly, sponsors could be economically incentivized to expeditiously
complete confirmatory trials and convert their applications to traditional approval.
What’s next? At the time of writing, the official docket for comments on this document was
not yet established. However, the typical 60-day opportunity for input on the guidance is
expected.

Featuring previous research by an Alexander Gaffney and Rachel Coe.

To contact the author of this item, please email Amanda Conti (aconti@agencyiq.com).
To contact the editor of this item, please email Alexander Gaffney (agaffney@agencyiq.com)

Key Documents and Dates

Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is
Underway
FDA Docket No.: FDA-2024-D-3334

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