The FDA has created a number of pathways to bring drugs for serious conditions onto the market sooner than the traditional approval process would allow. These include priority review, accelerated approval, fast track and breakthrough therapy designations, as well as emergency use authorizations, which are used in emergency situations, such as the COVID-19 pandemic.
One of the most popular routes is accelerated approval, which allows the agency to approve drugs using surrogate endpoints that are thought to predict a clinical benefit. Manufacturers bringing these agents to market must conduct confirmatory clinical trials, which may result in either a drug being withdrawn or the accelerated approval being converted to traditional approval.
The pathway was established in 1992, mainly to bring promising HIV/AIDS therapies to market sooner in order to combat the ongoing epidemic. Between 1992 and 2010, HIV drugs represented the majority of accelerated approvals. While only about one-third of drugs receiving accelerated approval during that time period were oncology drugs, that changed sharply over the following decade: From 2010 to 2020, 85% of the approvals were for oncolytics.
But some concerns exist around accelerated approval for oncology agents. One study published in August 2022 found that of the cancer indications given accelerated approval between Jan. 1, 2007, and Dec. 31, 2021, only 36% were rated as having high added therapeutic value compared with 53.3% for noncancer indications. Another study published in June 2018 revealed that of the 93 new accelerated approval hematology and oncology indications from Dec. 11, 1992, to May 31, 2017, 55% had completed confirmatory trials in a median of 3.4 years after approval, while 40% had not completed those trials. And yet another study published in September 2021 discovered that even after a negative confirmatory trial, one-third of indications remained on a cancer drug’s label, and half were rated the second-highest level of recommendation in National Comprehensive Cancer Network (NCCN) guidelines.
Industry experts have proposed numerous suggestions for ensuring that the pathway is truly achieving what it was meant to do: speed valuable medicines to patients who desperately need them.
Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence, has expressed interest in requiring manufacturers not only to communicate their confirmatory study plan early in the approval process but also to have these trials underway when they submit their applications for accelerated approval.
“Accelerated approval is aimed at the patients,” Pazdur said during the 2022 Friends of Cancer Research annual meeting. “It’s not an incentive program for the industry.”
Other suggestions include modifying some payment policies, such as increasing Medicaid rebates for accelerated approval drugs or economically incentivizing manufacturers to complete confirmatory trials, as well as providing a prompt withdrawal process if a company does not conduct required trials or the study does not confirm an agent’s benefit. Bipartisan legislation introduced in both the House and the Senate has included provisions to strengthen the pathway.
Amid the public outcry, the industry has seen an increase in voluntary withdrawals recently. Between 2011 and 2013, there were six withdrawals for accelerated approval oncology indications. But since Feb. 25, 2020, when the FDA granted Lilly’s request to withdraw the biologics license application for Lartruvo (olaratumab), almost 20 oncology indications and/or drugs themselves that had come onto the U.S. market via accelerated approval have been withdrawn, with the bulk of those withdrawals coming in 2021 and 2022. About half of the oncolytics impacted are immune checkpoint inhibitors that target programmed death-1/programmed death ligand-1 (PD-1/PD-L1) and have multiple indications.
Manufacturers with accelerated approval oncology indications should conduct their confirmatory trials and truly show that an indication provides value and is improving patients’ health. Otherwise providers may be reluctant to prescribe these agents, and the public calls for action on the pathway will continue to grow, perhaps resulting in outcomes unfavorable to pharma.
Additionally, the NCCN compendia recommendations are used to support Medicare coverage, meaning that Medicare will be required to reimburse use of these drugs. This has important financial consequences for patients—and the healthcare system overall.
Without proactive steps from the FDA, drugs that have no proven clinical value and known toxicities will continue to be used by patients and clinicians, who rely on the FDA to assess the risks and benefits of drugs. This also makes crowded markets even more crowded with drugs that have been proven ineffective. Since the FDA is not removing them from the market or the indication from the label quickly enough, education by manufacturers is important to understand an agent’s value—or lack thereof.