Accelerated approvals (AA): not so fast!

Authors:
Everardo D. Saad, MD, Medical Director and Consultant, IDDI
Marc Buyse, ScD, Chief Scientific Officer and Consultant, IDDI

The development of drugs and biologics is often a lengthy process that may take many years to complete successfully. Given the resources required during this time, it is no surprise that an accelerated approval (AA) is seen by several companies, particularly small and medium-sized biotechs working in oncology, as an ideal pathway to enter the US market and secure continued funding for their development.

In the current article, we discuss this strategy from regulatory and methodological perspectives, with an emphasis on the latest draft guidance on Accelerated Approvals (AA) in oncology by the US Food and Drug Administration (FDA).

What is accelerated approval?

Most drugs and biologics introduced globally are first approved by FDA and the European Medicines Agency (EMA).¹ Over the past three decades, both of these regulatory agencies have established special programs to expedite the development of drugs and biologics that may treat patients with serious conditions. The FDA has four expedited programs: AA, fast track, priority review, and breakthrough therapy; while Accelerated Approvals (AA) is an approval pathway, the other three programs confer “designation”—not approval—to the products in question.² The EMA has three programs for expediting development: accelerated assessment, conditional marketing authorization, and the priority medicines scheme, but these will not be discussed here.³

The AA pathway was introduced in 1992—during the HIV epidemic—for drugs intended for serious and life-threatening diseases. According to the FDA, a positive therapeutic effect that is clinically meaningful is called “clinical benefit”. The AA pathway may speed up approval on the basis of a surrogate endpoint deemed reasonably likely to predict clinical benefit or an intermediate clinical endpoint that can be measured earlier than irreversible illness or death.^4,5 Using surrogate or intermediate clinical endpoints can save time in the approval process, as shown by several cases of FDA approvals based on this definition of surrogacy.⁶ For example, instead of having to wait to analyze the overall survival of cancer patients, the FDA may grant AA to a drug based on the objective response rate (ORR), because tumor shrinkage is considered by the agency as reasonably likely to predict clinical benefit.⁷

In 2012, the US Congress passed the FDA Safety Innovations Act (FDASIA), whose Section 901 amended the Federal Food, Drug, and Cosmetic Act to enhance FDA authority to grant AA for drugs for serious conditions that fill an unmet medical need. More recently, as discussed below, US Congress enacted into law additional measures that impact the AA process.

One should note that drugs granted AA must meet the same statutory standards for safety and effectiveness as those granted conventional approval. Importantly, post-marketing confirmatory trials are usually required to verify and describe the anticipated effect on irreversible morbidity or mortality, or other clinical benefit conferred by products granted AA.⁴

Recent changes

The AA program has recently undergone increased scrutiny related to endpoints used for AA and their relationship to clinical benefit, the time to completion of confirmatory trials, and the process for withdrawing indications if confirmatory trials fail to show clinical benefit.⁵ In response to these concerns, AA reforms were included as part of the 2023 US Congress’ Consolidated Appropriations Act, which contains the Food and Drug Omnibus Reform Act (FDORA).⁹ According to Section 3210 of FDORA, no later than the date of AA, FDA must specify the conditions for a post-approval trial (or trials) required for a drug or biologic granted AA; such conditions may include target accrual and the trial protocol and milestones, including the target date of trial completion.

Other provisions include that sponsors must submit progress reports on the required post-approval trials every 6 months until study completion or termination; that FDA may use expedited procedures if a sponsor fails to conduct any required post-approval trial with due diligence; that if FDA does not require that the sponsor of a drug or biologic approved under AA conduct a post-approval trial, FDA must publish on its website the rationale for why such trial is not appropriate or necessary; and that within 18 months of the bill’s enactment, FDA must issue guidance documents covering AA-related topics, including on the identification and discussion in early-stage meetings with FDA of novel surrogate or intermediate clinical endpoints and on the use of novel trial designs for confirmatory trials.^9,10 In March 2023, FDA published its draft guidance titled “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics”.⁴

Despite the potential improvements to be accrued by implementation of FDORA provisions, concerns have been voiced regarding a certain lack of clarity or specific missed opportunities in the attempt to make AA a reliable and transparent process.^10,11 Moreover, it has been pointed out that FDORA is silent about the explicit allowance of the use of real-world evidence as confirmatory evidence of effectiveness and on the mandate that product labels for drugs and biologics disclose if they were granted AA.⁹ Regardless of these criticisms, sponsors should be aware of the main methodological implications of the new FDA guidance, which we summarize below.

What changes for trials leading to accelerated approval?

Given the nature of cancer and the ever-increasing number of new agents to treat it, AA has become an important approval pathway in oncology and malignant hematology. Importantly, before embarking on an AA plan, sponsors should conduct adequate dose-optimization and activity-finding studies.⁵

Drugs and biologics for cancer account for 66% of all FDA AAs during the first 25 years since the program inception, and nearly 85% over the past decade.^5,8 As a consequence of the very nature of this expedited pathway, single-arm trials accounted for 72% of AAs between 1992 and 2017, and only 28% of approvals were based on randomized trials. In single-arm trials, time-to-event endpoints such as progression-free survival and overall survival are not reliable, as the lack of a control arm precludes a distinction between the effect of an active drug versus that of a slow-growing tumor. As a result, slightly over half of all randomized trials and all the single-arm trials had ORR or one of its variations as primary endpoint.⁸

Despite the preceding discussion, in its latest guidance FDA highlights limitations of single-arm trials that may add uncertainty to the assessment of the benefit/risk of a product searching AA, stating that such an approval based on a single-arm trial may not be justified in a given clinical setting. Based on that, the document says that “a randomized controlled trial is the preferred approach to support an application for accelerated approval”.⁴ This is an important change in the agency’s recommendations attested by the fact that the word “randomized” was used only twice in the earlier guidance, and not in reference to the trial used to support AA.² Conversely, the section “Recommendations”, which occupies the bulk of the latest guidance, is divided into two parts: the longest is dedicated to randomized trials to support accelerated approval, and the shortest to single-arm trials.⁴

What changes for trials leading to accelerated approval?

Sponsors planning to pursue AA should also bear in mind that confirmatory trials are generally needed to confirm clinical benefit from a product eventually receiving AA. According to the earlier FDA guidance on expedited programs, if it was clear during development that a product was intended to be approved under AA, confirmatory trial(s) should be underway at the time the marketing application was submitted.² Unfortunately, at the time of the AA, sponsors frequently delay initiating these trials until AA has been granted.⁵

In the 25 years of experience with AA by FDA, 55% of oncology and hematology products granted an AA have fulfilled their post-marketing requirement and verified clinical benefit. On the other hand, 40% had not yet completed confirmatory trial(s) or verified benefit, while only 5% of the products had been withdrawn from the market.⁸ The median time to verification of clinical benefit and granting of conventional approval was 3.1 years, while the median time to withdrawal of an indication was 3.8 years. However, these medians varied according to whether the confirmatory trial had been initiated when the AA was granted. For products converting to conventional approval, the median time to such an approval was 3.0 years if the confirmatory trial was ongoing, versus 5.1 years if not. The median time to withdrawal was also longer if the confirmatory trial was initiated after AA: the median time to withdrawal was 3.8 years if the confirmatory trial was ongoing at the time of AA, versus 7.3 years if not. ⁵

What changes for confirmatory trials?

In the context of planning AA, the recent guidance says that “regardless of the approach under consideration, FDA recommends early discussion with the Agency before initiating and, as appropriate, during the conduct of, a trial(s).”⁴ The FDA generally encourages such discussions, even in the case of negative trials aiming at AA. In that context, FDA officials note that a trial not meeting its primary endpoint does not necessarily indicate that a drug is ineffective, given the many other potential reasons for such a failure. Moreover, if there are clear reasons why a trial aiming at AA may have failed and an unmet medical need still exists, FDA is willing to work with sponsors to identify subsequent clinical trials that could satisfy the AA requirement.¹²

In addition to the preference for randomized trials to support AA, the greatest novelty in the latest FDA guidance is the explicit proposal of two alternative strategies regarding the confirmatory trial. One strategy is the conventional separation between the trial used to support AA and the confirmatory trial, which would generally conform with the clear demarcation between phase 2 and phase 3 of development.^4,5 The other strategy, now named the “one-trial” approach, represents a potentially more efficient use of resources, even though at the potential expense of a larger upfront commitment on the part of stakeholders.

In the past, confirmatory trials were usually performed in a population with less refractory disease than the one typically assessed in trials supporting AA, since it was often difficult to initiate a randomized trial in the original population once the product was approved.⁵ The new guidance says that sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, to both support AA and verify clinical benefit.⁴ If that is done, AA may be granted on the basis of a planned interim analysis of an intermediate endpoint, such as ORR, and conventional approval granted on the basis of clinical benefit at trial conclusion.⁵

If the conventional strategy of two trials is pursued, FDA may consider a single-arm trial with ORR as primary endpoint in patients without other available therapies, and a concurrently-initiated randomized trial to demonstrate clinical benefit in patients with less refractory disease.⁵ If these trials enroll concomitantly—in which case the upfront commitment of resources would be the same or even larger than with the one-trial approach—, an interim analysis of safety and ORR in the confirmatory trial might provide supportive evidence and greater confidence for the AA based on the single-arm trial. Moreover, a clinically meaningful effect on ORR in the confirmatory trial might support an additional AA indication for the less refractory population. Importantly, in this and in other cases, the FDA and the sponsor would need to agree in advance on the success and failure criteria to be applied to the chosen strategy.

Conclusion

The AA pathway is an attractive option in oncology and malignant hematology. Pursuing this option entails understanding the associated regulatory requirements and methodological caveats related to dose optimization and trial design, particularly with regard to randomization in the trial leading to AA and the possibility to choose between the one-trial approach and a more conventional strategy. Also important are the explicit outlining of a sound development strategy and early, frequent, and transparent communication with FDA. This communication should address issues related to the target population, the primary and secondary endpoints, control of type-I error, and other methodological aspects which require sound statistical and regulatory knowledge and experience.

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