Anything Worth Doing Is Worth Doing Right: FDA Issues Draft Guidance on Requirements and Processes for Accelerated Approval

On December 5, 2024, the U.S. Food and Drug Administration (“FDA”) issued a much anticipated draft guidance for industry on accelerated approval that provides additional clarity on FDA’s expectations for accelerated approval endpoints and confirmatory trials as well as FDA’s process for withdrawing accelerated approval (the “Draft Guidance”). As part of the Food and Drug Omnibus Reform Act (“FDORA”), which was passed in late 2022, Congress had required FDA to issue guidance on various topics related to accelerated approval, including various considerations related to identifying surrogate or intermediate clinical endpoints, the use of novel clinical trial designs, and the procedures underlying the Agency’s newly granted expedited withdrawal process by June 2024; this guidance, though issued nearly six months after the anticipated deadline, is aimed at addressing these topics. FDA explicitly states in the Draft Guidance, however, that it also intends to issue further guidance on the accelerated approval process in the future.

The accelerated approval pathway aims to expedite the development and approval of drugs that provide meaningful therapeutic benefit to patients over existing treatments for serious or life-threatening illnesses or conditions. This pathway enables FDA to approve therapies for serious and life-threatening conditions based on a “surrogate” or “intermediate clinical” endpoint reasonably likely to predict clinical benefit. Sponsors of such drugs can thereby obtain approval more quickly than if they had to demonstrate an effect using traditional endpoints such as irreversible morbidity or mortality (“IMM”) or other clinical benefit, which generally requires longer-term studies.

This Alert summarizes key elements of and takeaways from the Draft Guidance.

Background

As a general matter, accelerated approval serves as an invaluable pathway to market for various infectious disease, oncology, rare disease, and other drugs. Accelerated approval is conditional, however, as regulations anticipate the completion of adequate and well-controlled confirmatory studies to verify efficacy or clinical benefit, which must be undertaken with “due diligence.”  If confirmatory studies fail, FDA may withdraw the drug from the market. This withdrawal process has traditionally been lengthy and onerous due to FDA’s limited statutory authority. As a result, numerous accelerated approval products have remained on the market despite a failure to verify clinical benefit. As of 2021, there were five “dangling” approvals (approvals for which confirmatory trials have been conducted that did not confirm clinical benefit) and three “delinquent” approvals (approvals for which the confirmatory trials missed both original and any revised milestones) still on the market, the oldest of which was approved in 1996.

To remedy this and to promote confidence in the safety and efficacy of marketed drugs, Congress granted FDA several new authorities related to accelerated approval in late 2022—including an expedited withdrawal process—as part of FDORA. FDA has also recently taken steps to promote transparency and confidence in the accelerated approval framework. In October 2021, FDA’s Oncology Center of Excellence (“OCE”) initiated Project Confirm, which established a searchable public database on the FDA website to provide the public with comprehensive information on the accelerated approval program in the oncology space.

Today, according to FDA databases, there are 108 accelerated approvals ongoing. FDA’s issuance of the Draft Guidance reflects the Agency’s continued commitment to facilitate understanding of the accelerated approval framework by the public and by industry actors.

Key Elements of the Draft Guidance

The Draft Guidance focuses most significantly on two topics: (1) FDA’s requirements and standards for granting accelerated approval, and (2) the procedures for withdrawing accelerated approval.

Granting Accelerated Approval

The Draft Guidance offers additional information regarding the key concepts underlying accelerated approval, including an explanation of appropriate endpoints to support accelerated approval, clarification regarding the applicable evidentiary standard, and an explanation of the requirements for confirmatory trials, discussed in detail below.

• Endpoints: The Draft Guidance explains that there are two types of endpoints that may be used as a basis for accelerated approval: “surrogate” and “intermediate clinical” endpoints. The Draft Guidance provides examples of both types of endpoints for various indications. FDA recommends that sponsors who intend to use novel surrogate or intermediate clinical endpoints as the basis for accelerated approval engage FDA early in the development process. Sponsors developing therapies for rare diseases should consider submitting a Rare Disease Endpoint Advancement (“RDEA”) Pilot Program proposal to collaborate with FDA on the development of a novel surrogate or intermediate clinical endpoint. In the context of rare diseases, FDA acknowledges that obtaining information on the correlation between a surrogate endpoint and clinical benefit can be challenging; as such, FDA will consider information from other available sources, including preclinical animal models, epidemiological data, and relevant clinical data.
• Evidentiary Standards: The Draft Guidance underscores that an accelerated approval application must meet the same standards for safety and effectiveness as those granted traditional approval and must also include adequate evidence that the proposed surrogate or intermediate clinical endpoint is reasonably likely to predict the intended clinical benefit of the drug. The Draft Guidance explains that FDA considers “all relevant evidence” in assessing a surrogate or intermediate clinical endpoint’s predictive value and provides examples of the types of factors that may be considered. These factors include the extent to which the pathophysiology of the disease and the role of the proposed endpoint in that pathophysiology are understood; whether there is reliable and consistent epidemiologic evidence supporting the correlation between the surrogate endpoint and the clinical outcome of interest; and whether there is clinical trial data supporting that the effect on the surrogate endpoint has been shown to predict clinical benefit with another drug or drugs. The Draft Guidance emphasizes that this assessment is case-specific and therefore does not provide guidelines on the specific clinical evidence that would be needed for particular surrogate or intermediate clinical endpoints.
• Confirmatory Trials: Sponsors receiving accelerated approval generally must conduct post-approval confirmatory trials to verify and describe the drug’s clinical benefit, and regulations require that such studies be carried out with “due diligence.” FDA makes clear in the Draft Guidance that “[a]ccelerated approval should not be considered if the completion of an adequate and well-controlled clinical trial to verify and describe clinical benefit will be infeasible.” The Draft Guidance recommends that sponsors consult with FDA regarding confirmatory trial design early in the development program, and that a protocol and timelines for the trial should be submitted to and agreed upon by FDA as early as possible. The Draft Guidance includes an express statement that 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 [emphasis added].” FDA intends to require that confirmatory trial(s) be underway prior to granting accelerated approval except in limited circumstances. This statement is largely in line with—though potentially more flexible than—prior statements by FDA, including in the 2023 draft guidance specifically related to Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics, where the Agency “strongly recommend[ed] that [confirmatory trials] be well underway, if not fully enrolled, by the time of accelerated approval action.” The Draft Guidance notes that FDA intends to address this issue in further detail in a separate guidance document. FDA also notes that the considerations outlined in previous guidance documents on the use of novel trial designs, including adaptive designs and centralized trials, remain applicable to confirmatory trials, including adaptive designs and decentralized trials.
• Other Conditions of Accelerated Approval: The Draft Guidance highlights additional requirements and conditions attendant to receipt of accelerated approval including information and disclosures required to be included in product labeling, and submission of promotional materials intended for dissemination or publication.

Withdrawing Accelerated Approval

Through the passage of FDORA, Congress granted FDA the authority to deploy expedited procedures to withdraw accelerated approval if certain conditions are met. Specifically, expedited withdrawal may be appropriate if (1) the sponsor fails to conduct any required confirmatory trial with due diligence; (2) a confirmatory study fails to verify and describe the predicated effect on IMM or other clinical benefit; (3) other evidence exists that the product is not safe or effective; or (4) the sponsor disseminates false or misleading promotional materials for the product. According to the Draft Guidance, should FDA be concerned that one or more of these criteria has been met, the Agency should discuss such concerns directly with the sponsor and seek an appropriate resolution, including the sponsor’s voluntary withdrawal or submission of additional data. The expedited withdrawal procedures under FDORA require the opportunity to convene an advisory committee to consider any proposed withdrawal, and the Draft Guidance recommends that FDA convene and consult such advisory committee to assist with determining whether any of the above criteria are met, prior to any proposal to withdraw approval.

If FDA determines that one or more withdrawal criteria has been met, the Draft Guidance provides a detailed overview of the expedited withdrawal procedures:

• Due Notice: Under the Federal Food, Drug, and Cosmetic Act (“FDCA”), FDA is required to provide the sponsor with due notice of its proposal to withdraw accelerated approval. The Draft Guidance clarifies that this should be in the form of a written notice with an explanation for the proposed withdrawal. Written notice should describe the opportunity for a meeting with and/or a written appeal to the Commissioner (or a designee of the Commissioner); information on how to submit an appeal; details regarding the Agency’s plan to publish a Federal Register notice seeking public comment on its proposal for withdrawal; and a time frame for the withdrawal process, including deadlines for the sponsor to submit a written appeal, request a meeting, or request an advisory committee.
• Opportunity for Public Comment: To satisfy the statutory requirement for an opportunity for public comment, FDA must publish a Federal Register notice that includes a copy of the written notice sent to the sponsor and the Agency’s explanation for the proposal to withdraw. According to the Draft Guidance, FDA generally expects that a 30-day comment window will be sufficient and the Agency “generally does not intend to extend the period of time to allow for public comment.”
• Opportunity for a Written Appeal: Under the FDCA, the sponsor must have an opportunity to submit a written appeal to the Commissioner or a designee of the Commissioner. The Draft Guidance clarifies that, where a designee is selected, the Commissioner generally intends to designate FDA’s Chief Scientist or one of the center directors for the Center for Biologics Evaluation and Research (“CBER”), the Center for Drug Evaluation and Research (“CDER”), or OCE who was not involved in the proposal to withdraw. In its written appeal, the sponsor should present its objections to the proposal to withdraw approval, and should include any supporting data, information, or evidence on which the sponsor relies to support its appeal. If FDA had convened an advisory committee when considering whether to withdraw approval, the sponsor should rely only on data, evidence, or analyses that were presented to such advisory committee, or else must show good cause for why such information was not provided (e.g., data were not available, or their significance was not reasonably foreseeable, at the time of the advisory committee meeting) and why it is material to the appeal. Written appeals should be submitted to the Federal Register docket.
• Opportunity for a Meeting: The FDCA also requires that sponsors be able to request a meeting with the Commissioner or the Commissioner’s designee. If a meeting is requested, it should be scheduled after submission of any written appeal and of any written responses from FDA or the sponsor. The Draft Guidance clarifies that this meeting is not expected to be decisional and instructs that meeting minutes be posted to the Federal Register
• Final Decision: FDA will issue a final decision based on the information filed in the docket for the withdrawal proceeding, information contained in the New Drug Application or Biologics License Application, and the record from the advisory committee meeting(s). The Draft Guidance clarifies that, upon a finding on appeal that the confirmatory studies do not verify clinical benefit or that the available evidence does not show the drug to be safe and effective under the conditions of use in the labeling, FDA generally intends to withdraw accelerated approval “in the absence of unusual circumstances.” The Draft Guidance describes what information should be contained in a decision by FDA, which includes an analysis of the statutory grounds for the proposed withdrawal, a summary of and responses to public comments, and an explanation for the basis of the decision. Notably, the decision will generally not address in detail the sponsor’s arguments as to why accelerated approval should not be withdrawn unless FDA determines that doing so is “warranted in the interest of completeness and transparency.” The decision should be posted to the FDA website and will be considered final and effective upon issuance.

Key Takeaways

While the Draft Guidance is an important resource for providing clarity on the expectations, processes, and timelines associated with obtaining and withdrawing accelerated approvals, various practical questions remain about FDA’s posture toward the accelerated approval process moving forward:

Potential for Additional Withdrawals: The Draft Guidance spends significant time explaining the process and timelines for withdrawing approval. Since the passage of FDORA, withdrawal of accelerated approvals, either by the sponsor voluntarily or by FDA, has occurred at a faster pace than ever before: according to FDA’s databases, of the 44 accelerated approvals that have been withdrawn, 25% (11) of those withdrawals have occurred since FDORA, including multiple high-profile withdrawals such as those for Makena and Pepaxto. Despite this trend, FDA has also recently indicated a willingness to show flexibility for “dangling” approvals in certain cases. While nine of the withdrawals since January 1, 2023, related to accelerated approvals for oncology therapies following an effort by FDA to identify “dangling” approvals in that space, a recent meeting by FDA’s Oncologic Drugs Advisory Committee discussed two specific “dangling” approvals for rare cancer indications and ultimately decided to allow the products to remain on the market while the sponsors complete additional studies.

Whether and how the second Trump administration—which has expressed an intention to nominate leaders to the Department of Health and Human Services who have raised concerns about the safety and effectiveness of certain marketed drugs, including some that may be subject to accelerated approval—might impact FDA’s approach to regulating ongoing accelerated approvals, including negotiating revised milestones for confirmatory trials, remains to be seen.

Importance of FDA Engagement: Though valuable for providing illustrative examples of surrogate and intermediate clinical endpoints and general considerations that FDA may use when assessing whether an endpoint is “reasonably likely” to predict clinical benefit, the Draft Guidance emphasizes numerous times that many considerations in the accelerated approval process are “case-specific” or “context-dependent,” and are therefore “not readily generalizable.” As a result, the Draft Guidance elects not to provide detailed guidelines on key issues like selection of novel endpoints and design of confirmatory trials, and instead instructs sponsors to engage directly with FDA early and often during the development process.

Additional Guidance: The Draft Guidance is not the first FDA guidance document related to the accelerated approval process. In recent years, FDA has published multiple guidance documents providing recommendations for seeking accelerated approval in certain specific contexts or disease states. See prior Ropes & Gray Alerts and podcasts for additional details. Additionally, CBER’s 2024 Guidance Agenda includes a planned draft guidance entitled, “Accelerated Approval of Human Gene Therapy Products for Rare Diseases,” which has not yet been published. The Draft Guidance should be read in tandem with these other more context-specific guidance documents. That said, the Draft Guidance currently represent FDA’s clearest explanation of the standards and requirements for complying with the accelerated approval regulations more generally, as well as of the process for expedited withdrawal of accelerated approval.

Interested parties may submit comments on the Draft Guidance by February 4, 2025. Ropes & Gray will continue to monitor developments in this area. If you have any questions about this Alert, please contact any member of our FDA regulatory practice or your usual Ropes & Gray advisor.