The accelerated approval (AA) pathway was introduced in 1992 (in response to the AIDS epidemic) to shorten the FDA approval process for drugs to treat serious or life-threatening diseases or rare diseases where there is a high unmet medical need. AA allows for drugs to be approved on the basis of surrogate endpoints that are “reasonably likely to predict clinical benefit.”1 Please see Part 1 of this blog series for an introduction to the accelerated approval pathway and Part 2 for more information on how surrogate endpoints for accelerated approval are identified and validated.
Although AA can speed access to potentially lifesaving drugs years earlier than traditional approvals, the tradeoff for this quicker access is a period of uncertainty regarding the true efficacy and safety while confirmatory evidence is gathered. Confirmation of clinical benefit is often achieved but is not guaranteed.
In Part 3 of our blog series on AA, we will dive into a controversial aspect of the accelerated approval pathway: confirmatory studies.
What is a confirmatory study?
The FDA requires that drugs initially approved under AA are subject to postmarketing confirmatory trials that can directly confirm the clinical benefit predicted by the surrogate endpoint. Confirmatory studies are typically agreed on between the sponsor and FDA ahead of time and formally established as a postmarketing requirement (PMR) for continued approval.2 Usually PMRs for AA indications include large, phase 3 randomized studies with primary endpoints that assess direct clinical benefit. Overall survival, for example, is often used in oncology studies as a direct measure of clinical benefit.2
While straightforward in principle, designing confirmatory trials presents many practical challenges that can impede the completion of the trial and/or complicate the interpretation of the results. Most importantly, it is not always feasible to enroll patients in confirmatory trials once the drug is already on the market, particularly for very rare diseases. For this reason, sponsors may need to consider a randomized confirmatory trial in a clinical setting that differs from the approved indication, such as an earlier line of therapy or, for rare diseases, a less rigorous single-arm approach may be used. The nature of what evidence constitutes a confirmation of benefit remains a heavily debated topic that is outside of the scope of this article; however, some of these challenges were presented at a Friends of Cancer Research Annual Meeting in 2020.3
When a confirmatory study reaches its primary endpoints, this fulfills the PMR, and the clinical benefit is considered to be verified; at which point the AA is generally converted to a full approval. On the other hand, in cases where a confirmatory study fails to confirm clinical benefit, or an appropriate confirmatory study could not be conducted, the AA may be withdrawn by the FDA. The FDA is not required to withdraw the AA; however, there is no time limit for completion of confirmatory trails defined in legislation or regulatory guidance.
Conversion of AAs to full approvals: Is the glass half-full or half-empty?
Two separate studies found that approximately 50% of all AAs have successfully converted to full approval.
- An investigation published in the British Medical Journal studied all 253 AAs granted by the FDA in the 28 years since the inception of the program in 1992, through 2020. Of these, 125 (49%) successfully confirmed clinical benefit, 44% had not yet completed confirmatory trials, and 6% had been withdrawn.4
- In a study focusing only on oncology AAs, the record is slightly better. Out of 93 oncology indications granted AA between 1992 to 2017, 51 (55%) had fulfilled their PMR within a median of 3.4 years. Forty percent of oncology indications had not yet completed confirmatory trials, and 5% had been withdrawn from the market.5
From a “glass half-full” perspective, half of all drugs approved under the AA pathway are successful—delivering promising, life-saving drugs to patients years sooner than traditional approval pathways, with verification of clinical benefit confirmed in a timely manner. In this context, the 5-6% of AAs that were withdrawn demonstrate a commitment to removing AAs that fail to confirm benefit.
However, from the “glass half-empty” perspective, nearly half of AAs had not yet confirmed clinical benefit. In the case of more recent AAs, confirmatory trials may still be ongoing. However, a small number of AAs had not yet started a confirmatory trial or had a failed confirmatory trial, yet they remained on the market. For critics, this is evidence that the FDA is allowing some AAs to “languish” in the pathway, without appropriate efforts to confirm clinical benefit. These critics believe that the number of AAs withdrawn should be much higher.
The most controversial situation with the AA pathway is the very small subset of AA drugs that have completed one or more confirmatory trials that failed to confirm clinical benefit, but the approval for that indication has not been withdrawn. These so-called “dangling approvals” often fall into a regulatory gray area, are a target of fierce criticism, and have been the subject of several FDA advisory committee meetings.
“Dangling” accelerated approvals: FDA advisory committee meetings
In April 2021, the FDA held a multi-day, multi-sponsor meeting of the Oncologic Drugs Advisory Committee (ODAC) to get expert advice on several immune-checkpoint inhibitors (“ICIs”) with dangling AAs. All the ICIs in question were PD-1/PD-L1 monoclonal antibodies. Each of these dangling AAs had failed to reach statistical significance on the endpoint of overall survival in one or more confirmatory trials. The FDA chose to use this meeting to publicly reevaluate these approvals. In the weeks leading up to the meeting, 4 of the indications were voluntarily withdrawn by the sponsors. Out of the 6 indications that were publicly reevaluated at the ODAC meeting, the panel voted against continued AA for 2 indications and voted in favor of maintaining AA for 4 indications.
Importantly, in the cases where the AA indication was withdrawn, it wasn’t because of a lack of benefit, or even a failed confirmatory trial, but rather that the treatment landscape had evolved, so that other treatment options were available. In short, the urgent unmet need that had originally justified the AA in these cases, no longer existed.
FDA advisory committee meetings are often a clue as to how the FDA is thinking about regulatory policy and how they may make decisions in the future.
What does it mean when a confirmatory trial fails? The FDA weighs in…
When a confirmatory trial fails to meet its endpoints, these data cannot be used to confirm clinical benefit or fulfill the PMR. However, a failed trial is not necessarily evidence that the drug is ineffective. In a perspective article published in The New England Journal of Medicine shortly before the April 2021 ODAC meeting, Dr. Julia Beaver and Dr. Richard Pazdur, from the FDA’s Oncology Center of Excellence, wrote:
“The fact that a clinical trial did not meet its endpoints does not necessarily mean that the drug is ineffective. A failure to demonstrate efficacy might be attributable to the selection of the primary endpoint, the power calculation, hierarchical statistical testing procedures, biomarker selection, trial design, or an inability to select the patients most likely to have a response. If there are clear reasons why a trial may not have achieved its primary endpoint and an unmet medical need still exists, the FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirement.”6 [emphasis added]
This perspective from the FDA provides an important clue into their thinking: unmet need is paramount. In many cases, drugs receive AA because there is an urgent unmet need. In these cases, the immediate removal of AA after a failed confirmatory trial could leave patients with severe or life-threatening diseases with no treatment options. So, while strict statistical requirements for fulfilling a PMR must be met, it is just as important for the FDA to weigh those criteria against the unmet medical need.
The AA pathway legislation allows for flexibility and discretion on the part of the FDA when enforcing PMRs for confirmatory studies. Proponents of AA, including the FDA itself, point out that this flexibility is necessary, given the complexity of these decisions and the need to balance benefit/risk with unmet need. Quoting the FDA, “the small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases.”6
However, critics believe there is too much flexibility in the pathway, resulting in arbitrary decisions that lack appropriate transparency, inappropriate use, and patients with serious diseases potentially being exposed to drugs that lack confirmed clinical benefit. Recently, these critics have called for reform of the AA pathway, and legislation is now being considered in Congress.
Coming next: Proposed reforms to the AA pathway
The AA pathway has far-reaching implications for patient access, coverage for new drugs under insurance plans and Medicare, and decisions made by sponsors in their clinical development strategy. In a future blog post, we will look in detail at proposed reforms that could impact the AA pathway and the surrounding regulatory landscape.
Angela W. Corona, PhD
Scientific Director, ProEd Regulatory
Angela is a Scientific Director for ProEd Regulatory. She is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University.
- US Food and Drug Administration. Expedited programs for serious conditions – drugs and biologics. May 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics
- For more information on the details of Postmarket Requirements (PMRs) for drugs approved under AA – an interested reader may wish to review the public PMR database maintained by the US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm
- Friends of Cancer Research Working Group. Optimizing the use of accelerated approval. 2020. https://friendsofcancerresearch.org/wp-content/uploads/Optimizing_the_Use_of_Accelerated_Approval-2020.pdf
- Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898. https://www.bmj.com/content/374/bmj.n1898.full
- Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618. https://jamanetwork.com/journals/jamaoncology/article-abstract/2673837
- Beaver JA and Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384:e68. https://www.nejm.org/doi/full/10.1056/NEJMp2104846