Oncology Time-to-Event Violations: Why regulatory policy matters and how policy analysis can predict future enforcement
Since announcing its “crackdown” on DTC pharmaceutical advertising, the US Food and Drug Administration has demonstrated a consistent enforcement focus on oncology presentations of time-to-event endpoints supported by single-arm trials. While enforcement letters in this area are becoming more frequent, the truth is that this regulatory focus predates the announcement of the Agency’s “crackdown” by several years. Since August 2024, the FDA has executed on an enforcement strategy targeting time-to-event endpoints that has resulted in over a dozen compliance letters. In the first of a two-part analysis, we explore the Agency’s regulatory policy regarding time-to-event endpoints based on single-arm trials. While the Agency has historically targeted promotion of time-to-event endpoints solely in the oncology space, understanding the Agency’s policy position is key to anticipating and preparing for future evolutions of this strategy that may expand beyond oncology products.
What are time-to-event endpoints?
Time-to-event endpoints measure the duration in time from a specified starting point or event (ie diagnosis, trial enrollment, treatment initiation, etc) to a specified ending event (relapse, disease progression, death, etc). In oncology therapies, overall survival and progression-free survival are key indicators of a drug product’s effectiveness. Time-to-event endpoints can only be assessed through a randomized trial that includes a comparator arm that controls for confounding factors that may also contribute to the intended treatment effect.
What is the FDA’s current policy position on efficacy endpoints based on Single-Arm Trials?
The FDA’s well-established policy position holds that single-arm trials do not adequately characterize time-to-event endpoints. The FDA’s 2018 final guidance titled Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics states that “because of the variability in the natural history of many forms of cancer, a randomized study is necessary to evaluate time-to-event endpoints.” The guidance was published in draft form in April 2005 and the Agency’s position regarding the use of randomized studies to evaluate time-to-event endpoints remains largely unchanged since then.
Expanding on the Agency’s existing policy, in March 2023, the FDA issued a draft guidance titled Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics. While the guidance highlights the Agency’s preference for randomized control trials to support accelerated approval in oncology products, it concedes that randomized control trials may not always be feasible or practical in the development of new cancer treatments. The guidance describes the Agency’s position regarding results generated from single-arm trials and how Sponsors can design oncology single-arm clinical trials to support approval under the accelerated approval pathway.
While single-arm trials commonly rely on objective response endpoints (i.e. the observed response of the tumor to treatment), the lack of a control group to serve as a comparator introduces several limitations. Importantly, the Agency states the following:
“Common time-to-event efficacy endpoints in oncology (e.g. tumor progression, survival) are generally uninterpretable due to failure to account for known and unknown confounding factors when comparing the results to an external control. FDA considers such endpoints exploratory and not adequate to be used as measures of efficacy in single arm trials intended to support approval.”
Timeline of Guidance Publication and Time-to-Event Enforcements
What endpoints are appropriate to demonstrate efficacy in single-arm oncology trials?
The 2023 guidance provides several recommendations regarding efficacy endpoints to support accelerated approval through a single-arm trial. First, Sponsors can demonstrate a drug’s anti-tumor potential through a measure of objective response rate (ORR) combined with a durable duration of response. The assessment of ORR should be based on appropriate criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) or other established clinical guidelines. Importantly, the Agency defines response rate as the combination of partial response (number of trial participants with observed objective reduction in tumor size as defined by assessment criteria) and complete response (number of trial participants whose tumor disappear). The guidance further states that “stable disease should not be a component of response rate” - a critical recommendation from that Agency highlighting that measures of clinical benefit that include stable disease over a specified period should be avoided.
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