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 Now, in a long-awaited draft guidance document, the FDA has for the first time described the criteria sponsors must meet to demonstrate that the study is “underway,” including granular plans and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.

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.
• 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). 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.
• 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.
• 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 “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)