When is a Confirmatory Trial “Underway” or Conducted with “Due Diligence” Enough for Accelerated Approval? FDA Explains Its New Authorities
January 30, 2025We recently blogged about a new December 2024 draft guidance about accelerated approval (the “December 2024 draft guidance”). That post largely focused on endpoints as well as the broader context for when accelerated approval is appropriate. However, as we note in that post, the design, timing of initiation, and timely conduct of confirmatory trials are also important considerations in FDA’s determination of whether accelerated approval is appropriate.
As a result of reforms enacted by the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), FDA’s authority to approve as well as withdraw an accelerated approval was given new regulatory “teeth” to ensure that confirmatory trials are conducted expeditiously. FDA’s withdrawal authority when a confirmatory trial is not conducted with “due diligence” was expanded to include that FDA could “specify the conditions for a postapproval study . . . which may include enrollment targets, the study protocol, and milestones, including the target date of study completion.” FDORA also gave FDA new authority to require that confirmatory trials be “underway prior to approval, or within a specified time period after the date of approval.”
To this end, the December 2024 draft guidance and a companion guidance published January 7, 2025, Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway (the “January 2025 draft guidance”) describe FDA’s latest thinking on what it means to conduct a confirmatory trial with due diligence. These draft guidances also discuss how the Agency plans to interpret whether such a study needs to be underway at the time of approval and, if so, whether it is “underway.” They also present a more intense focus on the timelines for confirmatory study initiation and completion as well as the feasibility of those studies to verify clinical benefit within those timelines.
For instance, the December 2024 guidance goes beyond the 2014 Expedited Programs for Serious Conditions – Drugs and Biologics guidance (the last to deal substantively with accelerated approval) to describe FDA’s expectation that sponsor’s take a proactive approach to ensuring confirmatory trials are completed within specified timelines. Similarly, the December 2024 draft guidance reiterates prior positions that confirmatory trials should generally be underway at the time the marketing application is submitted but also states that this recommendation becomes a requirement by the time of approval “except in limited circumstances.” However, it left unanswered what “underway” means, noting an intention to address this authority in the now published January 2025 draft guidance.
This blog post focuses on interpreting these new authorities with respect to timely conduct of confirmatory trials. We discuss, first, the way FDA articulated its thinking regarding what it means to conduct a confirmatory trial with due diligence and then how FDA intends to interpret that a study is underway. While the first topic is addressed primarily in the December 2024 draft guidance, the considerations and policies FDA articulates in the January 2025 draft guidance are also relevant. The January 2025 draft guidance, however, provides a more focused discussion of the timing of confirmatory studies and how that might impact approval.
Conducting with “Due Diligence”: How Sponsors Attend to the Resources, Monitor Progress, & Modify Study Designs to Complete Confirmatory Trials on Time
FDA’s authority to require confirmatory trials for a drug approved via accelerated approval have long included the ability to withdraw the drug for failure to conduct such trials with due diligence. This condition was included in the final rule for the original regulations, 21 CFR § 314 Subpart H (see the December 11, 1992 Federal Register, 57 FR 58958) as well as when the pathway was codified in the Federal Food, Drug, and Cosmetic Act by FDAMA (21 USC § 356(c)) in 1997. However, the meaning of “due diligence” has long been a question.
In its new guidances, FDA advises that sponsors should consult with the Agency regarding confirmatory trial design and conduct as early as possible with enough time to allow the trial to be underway at the time of approval. Sponsors should seek agreement on timelines for enrollment and completion, as well as that the design of the trial will ensure that it will be completed in these timelines. Considering FDA’s new authority to specify the conditions for such confirmatory trials (e.g., enrollment targets, study milestones), the December 2024 guidance states that FDA will specify these conditions “no later than the date of accelerated approval.”
The guidance provides key recommendations for sponsors that speak to the concept of conducting the trial with due diligence:
- Ensure all needed resources are provided to meet the specified timelines.
- Diligently monitor trial progress and be prepared to make appropriate modifications when enrollment is below expected levels or the trial is otherwise not progressing as intended (e.g., adding resources or sites, making other appropriate protocol changes).
- Take steps to facilitate high retention including by incorporating patient perspectives into the design of such trials.
FDA appears to be signaling that due diligence may not strictly mean abiding by completion timelines but also taking the steps necessary to try to make that happen. However, the due diligence requirements are only part of the equation, which is made clear by the publication of an entirely separate guidance interpreting FDA’s authority to require a confirmatory study be “underway” at the time of approval.
Accelerated Approval Can Be Denied if the Confirmatory Study Is Not “Underway” at the Time of Approval
As mentioned above, FDA can require a confirmatory trial to be “underway” prior to approval or within a specified time period following approval. The law did not define the term “underway,” which left some uncertainty as to what it meant (e.g., early planning steps, activating sites, opening enrollment, first patient dosed, halfway enrolled, fully enrolled) as well as to when FDA would, or would not, require a confirmatory study to be underway and whether that could change based on different circumstances.
In the intervening period of time, we have seen some hints as to how this might function. In November 2022, shortly prior to FDORA’s enactment, ADC Therapeutics announced that its plan to submit a BLA in 2023 for camidanlumab tesirine for relapsed or refractory Hodgkin lymphoma was delayed due to FDA’s “strong guidance” that a randomized confirmatory study “must be well underway and ideally fully enrolled” at the time of BLA submission. The study had not yet been initiated at the time of the announcement. In March 2024, FDA issued two complete response letters (“CRLs”) for Regeneron’s application for odronextamab for two lymphoma indications due to the enrollment status of the confirmatory trials. At the time of these CRLs, only a safety lead-in stage had been initiated for the confirmatory study, not the randomized confirmatory efficacy phase.
In contrast, although we are not aware of any examples of a confirmatory study having no patients enrolled at the time of approval since FDORA’s enactment (except for unique situations), we have seen a range of confirmatory study timing that has not prevented accelerated approval. On the low end of what could be considered underway was FDA’s approval of Amtagvi (lifileucel) in February 2024 for previously treated unresectable or metastatic melanoma. As stated in the Clinical Review memo, as of January 16, 2024, one month prior to approval, five subjects of a planned 670 were randomized and only two had undergone tumor resection, and 10 out of a planned 120 study sites were activated.
What Does “Underway” Mean?
The January 2025 draft guidance is intended to answer the question of what “underway” means, and the answer is … it depends. A confirmatory trial is considered to be underway when:
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. This target completion date is informed by the natural history of the disease, availability of alternative treatment, anticipated recruitment timeline, and the projected timeline for efficacy analysis(es);
2) the sponsor’s progress and plans for postapproval conduct of the trial provide sufficient assurance to expect timely completion of the trial. Specific considerations include participant enrollment to date (including the current and projected rate of enrollment), as well as the anticipated timeline for complete enrollment; the number of active sites to date and projected rate of additional site activation; and
3) enrollment has been initiated.
The January 2025 draft guidance also explains that when a single trial is designed to support accelerated approval with an earlier endpoint and verification of benefit with a longer-term endpoint, FDA will generally consider the confirmatory trial underway so long as the trial is expected to complete in a timely manner.
When Might a Study Be Required to Be More or Less “Underway?” And When Might a Study Not Be Required to Be “Underway?”
Certain factors may require some confirmatory studies to be more “underway” than others. For example, the January 2025 draft guidance states that randomization, which is often required to verify clinical benefit, may make confirmatory studies more difficult to conduct postapproval, particularly if there is a placebo arm. This is because patients may be less likely to enroll in a trial due to the potential to be randomized to the placebo arm or a potentially less effective active-comparator arm, while the newly approved treatment is commercially available. In such cases, if the Agency determines that continued enrollment/retention will be especially challenging, FDA may require enrollment to be complete at the time of approval.
Additionally, sponsors should consider factors that may adversely affect accrual, including the approval itself. The impact of approval may be greater if the confirmatory trial is in the same population as the approved indication, and not, for example, in an earlier disease stage. In such cases, the January 2025 draft guidance recommends that “all or a significant portion” of enrollment should be completed prior to accelerated approval. Given the impact of a potential approval to U.S. recruitment and retention, sponsors should also prioritize U.S. recruitment prior to approval, which should be closer to completion at the time of accelerated approval.
On the other end of the spectrum, the January 2025 draft guidance described certain circumstances where the confirmatory study may not need to be underway at all. Where randomization is not required due to, for example, “clinically relevant endpoints and disease natural history” in a rare disease context, the Agency has fewer concerns related to study completion if it is not underway prior to approval. Additionally, for some rare diseases “with very small populations with high unmet need,” there may be “unique challenges” with initiating confirmatory trials prior to approval.
FDA Expectations on Gaining Alignment & Setting Early Benchmarks
The January 2025 draft guidance recommends that, shortly after the End of Phase 2 meeting, there should be agreement between FDA and the sponsor on the design of the confirmatory trial. In practice, this seems ambitious, if not outright impractical, for situations where a novel surrogate or intermediate clinical endpoint is being considered (e.g., rare disease settings). In our experience, the focus of discussions at this stage is on filling gaps in the evidence to support that the endpoint is reasonably likely to predict clinical benefit. Discussions of the confirmatory study are often considered by FDA to be premature as there is not yet alignment on use of the accelerated approval pathway. In fact, often the very evidence that enables the endpoint to serve as the basis of an accelerated approval comes from a Phase 3 study, where the predictive value of the endpoint can be assessed using the interventional study data. It is also very difficult for sponsors to take the necessary steps to ensure a confirmatory study is underway with such uncertainty clouding the possibility of the accelerated approval itself.
Additionally, the January 2025 draft guidance provides that sponsors should propose early benchmarks to assist FDA in its determination of whether a study is “underway,” which may include recruitment goals, extent of site activation, and proportion of primary endpoint events accrued. Meeting these benchmarks prior to the accelerated approval action date would provide FDA with greater assurance of the trial’s feasibility and timely completion. If proposed benchmarks have not been met, FDA will consider whether accelerated approval is appropriate, taking into consideration any justification and plan to address delays.
Our Concluding Thoughts
The publication of the January 2025 draft guidance so close on the heels of the December 2024 draft guidance is critically important to helping sponsors navigate FDA’s new accelerated approval authorities. The absence of any specific guideposts for how FDA intended to define “underway” or “due diligence” since FDORA had resulted in significant confusion for sponsors. We now have a framework for how FDA plans to enforce these requirements, which is anchored to setting timelines for trial initiation and conduct. Consistent with recent FDA actions noted above, the guidances are signaling the Agency’s intention to use these authorities to ensure that clinical benefit be verified as quickly as possible and, if there is concern a program will not, to deny the initial accelerated approval. FDA has great discretion in what its expectations are for a study to be underway and conducted with due diligence. We now know that FDA can expect full enrollment of the study in some cases and merely expect initiation of enrollment in others.
We are also interested in the circumstances where FDA may not require a confirmatory study to be “underway.” One such situation is where randomization is not required in the context of a rare disease. As such, it appears that whether randomization will be required to confirm clinical benefit is very important for sponsors to know early in development, as this fact alone could shift the expectations for the confirmatory study from not needing to have begun enrollment at the time of approval to as much as full enrollment at the time of approval. We would encourage FDA to engage on confirmatory study design and share expectations as early as possible.
FDA also notes that a confirmatory study might not be required to be underway at the time of accelerated approval in the setting of diseases with “very small populations” with high unmet medical need. Additional clarity about how FDA intends to interpret “very small” would be very meaningful to sponsors in the rare disease space. Rather than draw a bright line, it would be helpful to consider the full clinical context in rare, serious diseases with unmet medical needs.
It also appears that in making its determination of whether a study is underway at the time of an accelerated approval action, much may depend on early benchmarks. While a footnote in the January 2025 draft guidance shares that the topic of “enrollment targets” and “milestones” will be discussed in another forthcoming guidance, we would advise sponsors to be realistic, but also conservative, in proposing justifiable benchmarks. It is difficult to predict with certainty how a trial will progress. We would also encourage FDA to be flexible in basing any adverse decisions on sponsors missing benchmarks and consider the factors expressed in the December 2024 draft guidance on whether the study is being conducted with due diligence even from that early stage. An agreement, a documented good faith effort, and open dialogue between sponsors and the Agency about such efforts and the difficulties encountered, we think, should carry significant weight in the short term to avoid regulatory action that may affect the availability of important treatments for patients.