FDA Issues New Draft Guidance for Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics

On December 6, 2024, the U.S. Food and Drug Administration (FDA or the Agency) released a draft guidance titled “Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics” (the Accelerated Approval Draft Guidance or Draft Guidance). The Draft Guidance, which complements FDA’s existing 2014 guidance on expedited programs,¹ discusses selecting appropriate surrogate and intermediate endpoints for sponsors looking to bring drugs and biologics to market through the accelerated approval pathway, provides some general information about meeting confirmatory trial obligations, and describes considerations and procedures related to expedited withdrawal of an accelerated approval under FDA’s newly enacted withdrawal authorities.

Background

Accelerated approval is intended to facilitate quicker development of drugs intended to treat serious and life-threatening conditions in areas of unmet medical need. Specifically, by using accelerated approval, FDA can meet the approval standard for drugs and biological products based on data demonstrating an impact on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit. By relying on endpoints that can be met earlier than clinical endpoints, sponsors and FDA can speed treatments to patients who need them and push additional work — that of verifying that the surrogate or intermediate endpoint is in fact predictive of clinical benefit — to post-marketing confirmatory studies.

The accelerated approval program was first established by FDA via regulation in 1992.² Building on the pathway’s success, Congress first codified these concepts into the statute as a pathway for “fast track products” and combined what we now call the fast track designation program with the accelerated approval pathway under section 506 of the FD&C Act.³ In 2012, the pathway was clarified and refocused. Congress disaggregated accelerated approval from fast track designation, clarified that the pathway could be used for any product intended to treat “a serious or life-threatening disease or condition,” and refocused use of accelerated approval “taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”⁴

Since then, accelerated approval has been used to support hundreds of approvals of original and supplemental new drug and biologics license applications. After a long-focused use in oncology,⁵ use of accelerated approval has become more diffuse across FDA. It is a focal point for gene therapy development, for example, and in rare disease drug development more generally.

All of this background seems to have informed FDA’s new Draft Guidance. Facially the Draft Guidance is focused on changes made by the 2023 year-end omnibus spending bill provision known as the Food and Drug Omnibus Reform Act (FDORA) — and indeed the Draft Guidance provides a good bit of additional clarity about topics that have been front of mind for Congress, patient groups, and other stakeholders, like FDA’s expectations for confirmatory trials and procedures for FDA’s expedited withdrawal of accelerated approval. It also, however, provides some very informative insights into how FDA is thinking about its overall use of accelerated approval, use of surrogates in specific contexts, and, critically, circumstances in which the Agency does not view accelerated approval as an option.

Summary of the Draft Guidance

The Draft Guidance opens with a history and overview of the accelerated approval pathway, including some of the benefits and risks of the pathway itself. Accelerated approval, FDA notes, “often allows sponsors to obtain approval for products intended to treat an unmet medical need sooner than would be possible under traditional approval,” but it also comes with risks that “inform the Agency’s decision-making regarding use of accelerated approval.”⁶ This includes risks that (a) a patient could be exposed to safety risks for a drug that ultimately does not have clinical benefit, and (b) because of the smaller and shorter clinical trials performed for drugs that have been approved through accelerated approval, there may be less information generated regarding rare or delayed adverse events.

As a result, the Draft Guidance explains, there are a number of conditions and requirements that are associated with accelerated approval:

• Sponsors must conduct postapproval studies to verify and describe the anticipated clinical benefit of the drug (a requirement that carries significantly more weight after FDORA gave FDA additional authority in this space and made it a prohibited act to fail to conduct any postapproval study “with due diligence” or to fail to submit “timely reports” with respect to such product).⁷
• On or before approval, FDA will specify the conditions for the postapproval studies, which, the Draft Guidance later explains, “should generally be underway” when the NDA or BLA is submitted.⁸
• Sponsors must submit reports on the progress of required postapproval studies approximately every 180 days and FDA is required to publish the information.
• The indications and usage section of drug labeling must include a brief description about the limitations and uncertainty associated with the clinical benefit of the drug.
• Sponsors must submit copies of all promotional materials to FDA.

The Draft Guidance also notes that accelerated approval should not be considered if it will not be feasible to complete an adequate and well-controlled confirmatory study, tying FDA’s statement about inappropriateness of the pathway in these conditions to the Agency’s discussion of its ability to withdraw an accelerated approval through an expedited process.⁹

The Agency appears to be building guardrails against increasing requests to consider accelerated approval — even if, as FDA acknowledges, it means that “[t]he accelerated approval pathway will not be an option for every serious disease with unmet medical need, particularly when the evidence is insufficient to support use of a surrogate endpoint or intermediate clinical endpoint, or when an adequate and well-controlled confirmatory trial would be infeasible.”¹⁰ Particularly important in light of the disciplined approach described in the Draft Guidance, the Agency also emphasizes the importance of communication between the sponsor and the Agency especially early in the drug’s development, in particular pertaining to issues of:

• The potential eligibility of a drug to be approved through the accelerated approval pathway
• Proposed surrogate or intermediate clinical endpoints and other clinical trial design issues
• Planning and conduct of postapproval confirmatory trials

Granting Accelerated Approval

The Draft Guidance goes to lengths to describe the types of surrogate and intermediate endpoints that the Agency may consider as a basis for accelerated approval (and those that it will not).

A surrogate endpoint that would be appropriate for accelerated approval, the Draft Guidance explains, can be a biomarker that is reasonably likely to predict a clinical benefit. A surrogate endpoint that is known to predict clinical benefit, however, would support a traditional (not accelerated) approval. And, in the absence of sufficient evidence to support reliance on a biomarker as having either a known or predicted impact on clinical benefit, neither traditional nor accelerated approval would be supportable. FDA advises that in such cases, sponsors should consult with the appropriate review division regarding a path forward.

Accelerated approval can also be supported by an intermediate clinical endpoint, i.e., a measurement of a therapeutic effect that can be measured earlier than irreversible morbidity or mortality — except that sponsors should first consider “whether the demonstrated therapeutic effect on the intermediate clinical endpoint alone would be a basis for traditional approval,” in which case the traditional approval pathway should be used. Approval based on intermediate clinical endpoints will be considered for accelerated approval only if it is critical to confirm the effects on irreversible morbidity or mortality (IMM) or other clinical benefits. The Draft Guidance also provides that early consultation should occur between review teams and sponsors when the sponsor intends to use a novel surrogate or intermediate clinical endpoint as the basis for accelerated approval. Sponsors should also seek early interactions with FDA since there could be additional preclinical or clinical data required to support the novel endpoints. FDA also notes that the Agency has established processes specifically for early consultation regarding new surrogate endpoints.

Evidentiary Criteria for Accelerated Approval

Although endpoints used to support accelerated approval differ from those used to support traditional approval, FDA emphasizes — as it did in the original accelerated approval regulations — that drugs approved through this pathway meet the same standards of safety and effectiveness as drugs approved through the traditional approval pathway. In addition to sufficient evidence of safety and effectiveness, the Draft Guidance explains, an application for accelerated approval should include adequate evidence that the proposed surrogate or intermediate clinical endpoint is reasonably likely to predict clinical benefit.

Whether or not a surrogate or intermediate clinical endpoint is reasonably likely to predict clinical benefit often requires a judgment call in conjunction with empirical evidence to support that relationship. With the caveat that the specific clinical evidence needed to support such a determination will be case-specific, the Draft Guidance outlines several important factors that will inform that judgment, including:

• How well the drug’s effectiveness on a clinical endpoint is understood. The clearer and more well-known the relationship, the likelier it is that the drug should go through the traditional approval process.
• Whether there is reliable and consistent evidence to support the correlation between endpoint and clinical outcome of interest with a particular attention placed on the source and nature of the evidence.
• Whether there is evidence from a clinical trial supporting that the effect on the surrogate endpoint has been shown to predict a clinical benefit with another drug. FDA emphasizes its expectation that “[c]linical data should be provided” to support the relationship.¹¹

As mentioned, however, the Agency also notes that this evaluation is context-dependent. For example, for rare diseases in which clinical trials to establish the surrogate-clinical endpoint relationship may not be feasible, there will be more emphasis on understanding the disease pathophysiology. And, FDA notes that the decision of whether accelerated approval may be supported by a particular surrogate endpoint will be informed by the magnitude and duration of the effect on the surrogate endpoint.

Confirmatory Trials

In FDORA, Congress granted FDA authority to require initiation of a confirmatory clinical trial prior to accelerated approval, and also to specify the conditions for postapproval studies (e.g., enrollment targets, study protocols, milestones, and study completion target date) at the time of the accelerated approval. The Draft Guidance explains FDA’s thinking on both of these points. It explains that except in limited circumstances, FDA intends to require that confirmatory trials be underway by the time the marketing application is submitted and before FDA will grant accelerated approval. The Agency further explains that on or before the approval, FDA will set conditions and a timeline regarding the progress of the confirmatory trials. Moreover, the Draft Guidance stresses that confirmatory trials must be completed with due diligence, with the Agency defining due diligence as the commitment by the sponsor of “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.”¹² FDA seems to be adopting a “no excuses” policy, noting that sponsors should expect to add resources, add sites, or make other appropriate protocol changes in order to ensure progress and completion of confirmatory trials.

FDA’s expectation is that the confirmatory trial will be conducted in the same patient population for which accelerated approval was granted. The Agency does acknowledge, however, that sometimes flexibility will be necessary in confirmatory studies. For example, there will be times when the confirmatory trial may need to be conducted in a different but related population that can verify the predicted clinical benefit — for instance, in a population with a different stage of the same disease as is often the case in oncology. There will also be times when novel approaches in study designs may be permissible, although the Agency cautions that sponsors should discuss such novel approaches with the FDA before creating the trial design. FDA also notes that in some circumstances a confirmatory trial may comprise additional analysis of the surrogate endpoint itself, rather than the clinical endpoint. And relatedly, FDA acknowledges that in some cases the same clinical trial may be able to both support the accelerated approval and fulfill a confirmatory trial requirement, for example where the surrogate endpoint can be measured earlier in the trial to support accelerated approval and then either that or additional endpoints measured later to confirm clinical benefit.

Other Conditions of Accelerated Approval

The Agency again stresses in the Draft Guidance that the drug labeling must describe the limits on efficacy and uncertainty related to clinical benefits for drugs that have received accelerated approval.¹³ Additionally, all promotional materials intended for dissemination or publication within the first 120 days following marketing approval must be submitted to FDA for preapproval review; after that, the applicant must submit promotional materials to FDA at least 30 days prior to the intended time of initial dissemination of the material unless otherwise informed by the Agency.

Withdrawal of Accelerated Approval

The section of the Draft Guidance on withdrawal of accelerated approval implements new authorities related to the expedited withdrawal of accelerated approvals as added by FDORA.¹⁴

In the Draft Guidance FDA outlines the circumstances under which the Agency will withdraw accelerated approval using expedited procedures:

• The sponsor fails to conduct any required postapproval study
• The study fails to verify any clinical benefit
• Other evidence demonstrates that the drug is not safe or effective
• The sponsor uses false or misleading promotional materials for the drug

The Draft Guidance further provides that FDA expects that any proposal to withdraw approval will be issued by the FDA Center or Centers that approved the drug, and it advises that officials within the Center should seek to speak with the drug sponsor and attempt to come to a resolution before withdrawal is proposed. The guidance explains that the Center also generally should convene an advisory committee prior to putting forth a proposal for withdrawal (note that the sponsor may request such an advisory committee as part of the withdrawal, as well).

Finally, the Draft Guidance walks through the procedures that the Agency will undertake to provide due notice and explanation of the proposed withdrawal to the sponsor, including the written appeal process and the opportunity to meet with the FDA Commissioner or a designee of the Commissioner. The guidance’s focus on expeditious resolution of any pivotal issues is notable, if not unexpected. For instance, the Agency notes that a sponsor may be deemed to have waived its opportunity to participate in the proceedings — including its opportunity to submit an appeal and supporting materials, request a meeting with the Commissioner/designee, or request the convening of an advisory committee — if it does not pursue such opportunities within the timeframes allotted.

Conclusion and Key Takeaways

In addition to clarifying how FDA proposes to implement the new authorities and requirements of FDORA, FDA particularly emphasizes two important issues in the Draft Guidance.

First, that confirmatory trials need to be conducted according to the timeline and conditions of study that the Agency specifies. FDA, Congress, and the Office of Inspector General have each expressed frustration in the past regarding delays of confirmatory trials (as well as with other aspects of the accelerated approval program),¹⁵ which is reflected in FDA’s new authority to require that a confirmatory trial be underway prior to accelerated approval or within a specified time period after the date of accelerated approval (not to mention that it is now a prohibited act to fail to conduct the confirmatory trial with diligence). The Draft Guidance indicates FDA will seek to apply this authority strictly and as a matter of course.

Second, the Agency goes into significant detail discussing the types of endpoints that should and should not be used as the basis for accelerated approval, significantly expanding upon the similar discussion in the 2014 final guidance and again stressing the importance of taking great care to ensure the endpoints ultimately used in the accelerated approval study are appropriate (and, by inference, to shore up the Agency’s refusal to consider accelerated approval when it deems endpoints to be inappropriate). Also of note is the focus in the Draft Guidance on the idea that validated surrogates should be used to seek traditional, not accelerated, approval.¹⁶

It is also worth noting that the Draft Guidance’s discussion of the expedited withdrawal procedures established by FDORA marks an important milestone. FDA has had statutory authority to withdraw approval, via expedited procedures, of drugs approved via the accelerated approval pathway and its predecessor pathways since passage of the Food and Drug Modernization Act of 1997 and in regulations before that.¹⁷ In practice, however, FDA has most often sought voluntary withdrawal¹⁸ rather than undertake the fraught exercise of an “expedited” withdrawal — which historically has not been terribly expedited. Now, the FDORA amendments arguably have set the stage for a streamlined process on both sides. The sponsor will be allowed an opportunity to meet with the FDA Commissioner or their designee, a period of public comment on the withdrawal proposal, and an opportunity to submit a written appeal to FDA personnel who had not participated in the proposed withdrawal of approval; the Agency will be able to more expeditiously withdraw approval where it believes it needs to. This may result in new incentives on both sides. Sponsors may be more reluctant to engage in the FDORA process rather than capitulate to FDA’s request for voluntary withdrawal. FDA may be more willing to use the withdrawal mechanism more aggressively knowing that it can more easily pivot. This newfound ease should, in turn, make FDA more willing to use accelerated approval aggressively to speed treatments to patients, as it was originally intended.

Comments are due to FDA on the Draft Guidance by February 4, 2025. If you have any questions about the content discussed here or would like more information, please reach out to one of the authors of this Advisory or to your existing Arnold & Porter contact.

© Arnold & Porter Kaye Scholer LLP 2024 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.