FDA’s new accelerated approval guidance offers detail on withdrawals process, but punts on confirmatory studies

A long-awaited draft guidance document on accelerated approval unveiled today by the FDA offers some new details about the agency’s “expedited” withdrawal process that is anything but fast. But for sponsors who were hoping to learn new details about what the agency wants to see as part of confirmatory studies initiated prior to approval, the agency’s guidance has a simple message: Please wait for further guidance.

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 ensure 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.
• However, 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.

Now, FDA has published a draft procedural guidance interpreting some—but not all—of these FDORA reforms.

• AgencyIQ has been anticipating the document’s publication for some time. As mentioned above, FDORA established a June 2024 publication target that was missed. In July, AgencyIQ reported on the White House’s Office of Information and Regulatory Affairs (OIRA) announcement that it received a draft guidance from the FDA titled, “Expedited Program for Serious Conditions – Accelerated Approval of Drugs and Biologics,” which we interpreted to be the guidance called for by Congress. [ Read AgencyIQ analysis here.]
• On December 5, 2024, FDA published that guidance document. The draft procedural guidance spans 25 pages and contains detailed background information on the legislative foundations for FDA’s authorities surrounding the accelerated approval pathway. The document hits the marks laid out in FDORA without venturing outside the bounds. The bulk of the document addresses two topics: (1) granting, and (2) withdrawal of accelerated approval.

FDA’s new guidance: Granting accelerated approval

• FDA uses this section to elaborate on its interpretation of multiple statutory requirements. First, it describes in detail the two types of endpoints that can be used as a basis for accelerated approval, surrogate and intermediate endpoints. Bulleted examples of endpoints that have successfully supported accelerated approvals are provided for a variety of indications. The guidance describes in mostly broad strokes how including FDA’s determines whether these endpoints meet the “reasonably likely to predict clinical benefit” bar. Both types of endpoints will be evaluated in a “context-dependent” manner.
• A clear statement on confirmatory trials: “FDA has interpreted the due diligence requirement to mean that sponsors must commit sufficient resources to conduct the trial(s) intended to verify the clinical benefit expeditiously so that a determination of whether the drug provides the expected clinical benefit can be made as soon as possible.”
• Next, the guidance describes some new authorities regarding confirmatory trials. FDA states 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.”
• FDA provides a deep dive on confirmatory studies with an emphasis on innovative trial approaches. This was a specific requirement of the guidance per FDORA. “In general, the considerations described in FDA’s guidance documents on the use of novel trial designs in the development and regulatory review of drugs and biological products can be applied to the design of confirmatory trials,” the document states, specifically calling out adaptive designs, enrichment strategies, trials with pragmatic elements, and decentralized trials as examples. [ See AgencyIQ’s analysis of an FDA/Duke-Margolis workshop for additional background on these approaches.] That said, sponsors are encouraged to discuss these plans with the agency early, and leverage available communication channels like its Complex Innovative Trial Design Meeting Program [ See AgencyIQ’s analysis of that program here.].
• Surrogate endpoints and rare diseases: The guidance offers some interesting commentary on the use of accelerated approval for products intended to treat rare diseases and conditions. FDA notes that obtaining information regarding the correlation between the surrogate endpoint and the extent of improvement can be challenging to obtain for rare diseases. “In such circumstances, FDA will weigh information from other available sources, including preclinical animal models, epidemiological data, and relevant clinical data, to determine if the convergence of evidence supports the surrogate as reasonably likely to predict the intended clinical benefit,” FDA explained.
• The section concludes with some important administrative and timing considerations regarding labeling, promotional materials, and post marketing recordkeeping for products granted accelerated approval. As discussed above, FDORA gave FDA authority to require more regular reports (i.e., every 180 days) from sponsors regarding progress toward confirmatory study milestones. This was not addressed in the guidance, which stated that “The Agency intends to address this authority in a separate guidance.”

Second: Withdrawing accelerated approval

• The guidance reviews the new statutory requirements for expedited withdrawal, which can be used if one of four conditions are met: (1) the sponsor does not conduct any required post approval study of the product with due diligence, (2) the study fails to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical benefit, (3) other evidence that the product is not safe or effective, or (4) the sponsor disseminates false or misleading promotional materials for the product.
• The law outlined the official sequence of actions FDA can take for expedited withdrawal procedures, and the guidance interprets and expands on each one. However, FDA makes clear in guidance that the initiation of the procedure should not come as a complete surprise to sponsors, as explained below.
• Preliminary discussions. “When the data or other information received by the Agency raises concerns that one or more of the criteria for withdrawing approval may have been met, responsible officials within the Center should discuss their concerns with the sponsor and seek an appropriate resolution,” it states. FDA says that these preliminary discussions may result in voluntary withdrawal, or the submission of additional data the sponsor considers to be relevant.
• The guidance explains that FDA should use an advisory committee at this stage to weigh in on whether one or more of the four withdrawal criteria was met in order to “provide an opportunity for a robust, public discussion of the issues.”
• If one or more conditions has been met, FDA begins the expedited withdrawal process by formally notifying the sponsor, offering an explanation and some options. FDA issues a proposal to withdraw approval.” The guidance lays out the minimum information that the proposal should contain. The sponsor should be offered an opportunity for a meeting with and/or a written appeal the Commissioner or the Commissioner’s designee. The sponsor should also be informed of whether an advisory committee was previously convened on the proposed withdrawal (AgencyIQ expects that the sponsor would be well aware if that is the case). If not, the sponsor can request one. FDA should request a response with the sponsor’s chosen course of action, providing instructions and a timeframe “that is reasonable under the circumstances.” In the proposal, FDA should inform the sponsor of plans to publish a notice in the Federal Register seeking public comment on the proposal.
• Who can be the Commissioner’s designee? Per statute, this can be an individual selected by the Commissioner who was not involved in the proposal or subordinate to someone who was involved. According to the guidance, “the Commissioner generally intends to designate FDA’s Chief Scientist or one of the center directors of the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, or the Oncology Center of Excellence.” This person can assemble a team of advisors to help with review.
• The Federal Register docket seems to serve as a central hub for all communications related to the expedited withdrawal process, as explained below. The guidance states that it should be open to the public for a 30-day period. While this is a relatively short comment period by FDA’s standards, the guidance clarifies that FDA “generally does not intend to” grant extensions.
• The written appeal and agency response. The sponsor should submit its written appeal and supporting materials to the Federal Register docket. This appeal should present the sponsor’s objections, including “any supporting data, information, or evidence.” If an advisory committee was convened prior to the formal proposal to withdrawal, the sponsor should rely on the information it presented at that meeting in the written appeal. If the sponsor submits new data, evidence, or analyses, they should have “good cause,” which the agency explains refers to information that was not reasonably available or reasonably foreseeable at the time of the prior meeting. The Center that proposed the withdrawal will have an opportunity to respond to the appeal in writing.
• Meeting with the Commissioner or the Commissioner’s designee. If the sponsor elects to have this meeting, the guidance explains that it should take place after the submission and response to the written appeal. The meeting can include presentations from the sponsor as well as the Center who proposed withdrawal. However, the guidance notably emphasizes that, “The meeting is not expected to be a decisional meeting,” and that minutes should be posted to the public docket.
• The FDA may convene an advisory committee during the latter stages of the process, though this will only occur if no meeting has occurred thus far. In AgencyIQ’s view, this seems like a rare scenario since the guidance says an advisory committee meeting should occur prior to issuing the proposal to withdraw.
• Finally, a decision. The guidance makes clear that the “Commissioner/designee’s decision on the appeal should be based on information filed in the docket…” The final decision should include specific information: the statutory grounds for withdrawal, a summary of and response to public comments, and an explanation of the decision on whether the proposal to withdraw approval will be finalized. This decision will be considered both final and effective upon issuance. The guidance explains that if a sponsor waives its right to the process at the outset, the decision will be made following the Federal Register period.

Analysis

• Expedited withdrawals don’t mean fast: FDA’s additional information about the process of withdrawing a drug from accelerated approval demonstrates well something that AgencyIQ had already written about: This is not a “quick” process. While the process is faster than what it had been before, the withdrawal process provides sponsors with considerable rights and privileges which can result in a long, drawn-out appeals process, which only takes place after an initial process to withdraw the drug. Because the process is so onerous, we expect that FDA will chose to employ it as a last resort, and instead ask most companies to voluntarily withdraw products (or change labeled indications) before.
• This document should be read as being part of FDA’s ecosystem of accelerated approval guidance. In line with the new guidance’s emphasis that many aspects of accelerated approval are “context-dependent,” FDA has released multiple product-class specific guidance documents. In March 2023, OCE published its thinking on Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics [ See AgencyIQ analysis here.] In more granular cases, 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.]. And the agency has its foundational guidance on accelerated approval and other expedited programs, which it published in May 2014.
• But what is interesting is how this guidance on accelerated approval differs in some meaningful ways from the OCE’s guidance on accelerated approval in oncology. For example, 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.
• We are expecting further guidance on accelerated approval and other related topics soon. As AgencyIQ recently discussed, a new draft guidance entitled “Accelerated Approval of Human Gene Therapy Products for Rare Diseases,” remains on CBER’s 2024 guidance agenda and could be published in the near future. The new guidance also previews additional guidance under development by FDA on the topic of confirmatory studies, which could help explain the extent to which FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) align with the confirmatory trial recommendations made by the OCE in its accelerated approval guidance.
• What types of products will be impacted by these new processes? FDA’s previous posture toward certain “dangling approvals” provides a clue. In November 2023, FDA’s Oncologic Drugs Advisory Committee (ODAC) convened to discuss two “outlier” accelerated approvals with years-overdue confirmatory studies. The products at hand, which were indicated for rare cancers, had accelerated approval confirmatory studies that have been ongoing for over 14 and nine years respectively. Nonetheless, FDA clarified that products would remain on the market, instead asking its advisors to discuss strategies to promote timely completion of the studies. FDA may maintain this approach for the rare disease setting but opt to flex its new authorities in other contexts. [ Read AgencyIQ’s full analysis of that meeting here.].
• Congress is likely to remain interested in the rollout and implementation of these reforms amidst election upheavals [ See AgencyIQ’s curated collection related to the election and transition here.]. This is because the FDORA reforms stemmed from the May 2022 introduction of Rep. FRANK PALLONE’S (D-NJ-06) Accelerated Approval Integrity Act, which ultimately became a blueprint for the legislation. Pallone retained his seat in the 2024 election, and will likely head the minority for the powerful (and evolving) Energy and Commerce Committee in the 119th Congress.
• What’s next? The comment period for the draft guidance will close Feb. 04, 2025.

Featuring additional analysis by Alexander Gaffney and previously published research by 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 – Expedited Program for Serious Conditions
• Docket No.: FDA-2024-D-2033
• Comment period closes Feb. 4, 2025