The accelerated approval pathway was established in 1992 to expedite access to new therapies for patients with serious or life-threatening diseases. First created as a strategy to rapidly address unmet medical need during the HIV-AIDS crisis, oncology drugs now comprise the largest proportion of accelerated approvals. Use of this pathway allows the FDA to grant approval sooner based on surrogate endpoints that are reasonably likely to predict clinical benefit. But the caveat is that the sponsor is required to carry out confirmatory clinical trials to verify the clinical benefit, after approval. Timely completion of the post-approval confirmatory trials is imperative to ensure that therapies approved via this pathway are safe and efficacious.
In 2017, when my coauthor and I decided to analyze the fulfillment of post-marketing requirements for confirmatory clinical trials among recent accelerated approvals of oncology drugs, I thought we might find that some trials were delayed. After all, a US Government Accountability Office report a few years earlier had concluded that delays were common among post-approval studies overall, and through my own experience in drug development, I was keenly aware of the many challenges inherent in conducting cancer clinical trials.
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Marjorie Zettler Marjorie Zettler, PhD, MPH is Executive Director of Clinical Science at Regor Pharmaceuticals, Inc. and a 2022 Woman Worth Watching® in STEM. An award-winning industry veteran with two decades' experience in clinical research, drug development, and regulatory strategy, she has published over 100 abstracts, manuscripts, book chapters and patents.
Our study found that for the 6-year period analyzed, confirmatory clinical trials were on schedule. However, we were surprised to discover that for 3 accelerated approvals (all involving immune checkpoint inhibitors), the trials had been completed but missed their primary endpoint. In all 3 of those cases, the drug was still on the market for the indication in question, with no action by either sponsor or FDA to withdraw it. This was unexpected: the fail-safe built into the accelerated approval pathway is that the approval can be withdrawn if confirmatory trials fail to verify clinical benefit. How had these 3 slipped through the cracks?
Concerns over the accelerated approval pathway deepened in subsequent years, as further questions arose regarding how clinical benefit was being assessed in confirmatory trials, and whether some endpoints commonly used to support accelerated approvals of cancer drugs were even valid surrogates of clinical benefit at all. Amid growing criticism, FDA’s Oncology Center of Excellence undertook a re-evaluation of the program. In 2021, a day of reckoning came for 10 “dangling” accelerated approvals of immune checkpoint inhibitors: after discussions with sponsors, 4 were voluntarily withdrawn from the market for the specific indication, while 6 others were reviewed at an Oncologic Drugs Advisory Committee meeting in April of that year. The Committee voted to maintain 4 of the 6 approvals. Project Confirm was launched in October 2021 to promote greater transparency of the accelerated approval program with respect to oncology indication approvals. Trackers on the site provide up-to-date information on accelerated approvals with ongoing confirmatory trials, those for which trials have verified clinical benefit, and those that have been withdrawn.
In September 2022 an investigation by the Office of Inspector General of the US Department of Health and Human Services found that over one-third of drugs granted accelerated approval (across all indications) had incomplete confirmatory clinical trials, some delayed by years. The report estimated that Medicare and Medicaid have spent more than $18 billion from 2018 to 2021 for drugs that were approved via the accelerated approval pathway but were overdue in completing clinical trials to verify clinical benefit. It also reported that half of all accelerated approval withdrawals took place after January 2021.
In December 2022, the Food and Drug Omnibus Reform Act (part of the Consolidated Appropriations Act, 2023) was enacted. Section 3210 of this legislation (“modernizing accelerated approval”), gives FDA more authority to specify the details of confirmatory clinical trials, and to require that studies be underway at the time of accelerated approval. Importantly, the legislation allows for FDA to take enforcement action against sponsors who fail to conduct confirmatory trials on schedule, and describes “expedited procedures” for FDA to withdraw accelerated approvals.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
On March 24th, FDA issued a new draft guidance on clinical trial considerations to support accelerated approval of oncology therapeutics. The guidance describes more robust trials, and shorter timelines between approvals and completion of confirmatory clinical trials. Notably, the guidance states that randomized controlled trials are the preferred approach for accelerated approval (historically, single arm trials have frequently been used to support accelerated approval of oncology therapies). While this guidance was not listed on the CDER Guidance Agenda for 2023, the agenda does include an administrative/procedural guidance entitled “Civil Monetary Penalties for Failure to Meet Accelerated Post Marketing Requirements”, further signaling FDA’s intent to take a tougher stance.
Nearly 6 years have elapsed since my coauthor and I first conducted our analysis. Some things haven’t changed: risk is still implicit in the accelerated approval pathway, and there will always be trade-offs between earlier patient access to potentially lifesaving or life-extending therapies and the possibility of toxicity or lack of efficacy. But over the past 2 years, concerted efforts have been undertaken by policymakers and FDA’s Oncology Center of Excellence to mitigate those risks and improve the transparency of the accelerated approval program. These actions are crucial to restoring public trust – trust that has suffered considerable erosion. The accelerated approval pathway is a critical mechanism by which new therapies for serious or life-threatening conditions like cancer can reach the patients who need them, faster. The changes we are witnessing attest to FDA’s commitment to protecting the integrity of the program, and usher in a new chapter for accelerated approval in oncology.
Photo: Michail_Petrov-96, Getty Images
Marjorie Zettler, PhD, MPH is Executive Director of Clinical Science at Regor Pharmaceuticals, Inc. and a 2022 Woman Worth Watching® in STEM. An award-winning industry veteran with two decades' experience in clinical research, drug development, and regulatory strategy, she has published over 100 abstracts, manuscripts, book chapters and patents.
