Interventions Are Needed to Prevent Clinical Trial Failure in HNSCC

Clinical trials evaluating treatments for patients with head and neck squamous cell carcinoma (HNSCC) are often terminated early due to strategic decisions or poor recruitment, underscoring the need for updated recruitment schema, better data monitoring practices, and other interventions, according to findings from a study conducted by a research team from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine in Florida, which were published in JAMA Otolaryngology–Head & Neck Surgery.¹

Findings from the retrospective study revealed that of 692 matched trials that were analyzed, 346 failed and 346 were completed. The leading reasons for trial failure included sponsor-driven decisions (29.5%) and poor recruitment (26.0%). Strategic decisions were the most common reason for failed phase 1 studies (n = 47 of 111; 42.3%). Poor recruitment was the most common reason for failure for phase 2 (n = 57 of 190; 30.0%), 3 (n = 9 of 41; 22.0%), and 4 (n = 4 of 4; 100%) trials.

“Classically, when we speak about clinical trial failures, we equate a failure to not reaching a primary end point or not reaching FDA approval,” the study research team said in a statement to OncLive^®. “This is especially relevant to the common statistic that 90% of drugs fail clinical drug development. We sought to focus on the understudied and significant portion of trials that are terminated and withdrawn. These trials do not reach the finish line and therefore represent a significant loss of resources and potentially beneficial clinical therapies.”²

The research team was comprised of Elizabeth J. Franzmann, MD, FACS; Alex Reznik, BS; and Janice Huang, MS. Franzmann is a professor of otolaryngology and the director of head and neck research at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. Reznik and Huang are MD/PhD candidates at the University of Miami Miller School of Medicine.

How was the analysis conducted?

The cross-sectional case-control study identified interventional clinical trials for the treatment of patients with HNSCC conducted between January 1, 2000, and December 31, 2024, via ClinicalTrials.gov.¹ The study authors defined failed studies as those with terminated or withdrawn status. Failed trials were matched with completed study controls via a 1:1 nearest-neighbor propensity score method based on trial phase.

“The main objective of our study was to identify actionable insights into trial characteristics associated with failure because we reasoned this could help the targeted design of trials that would avoid these pitfalls,” the research team explained.

What were the additional findings, and how could they inform future trial design in HNSCC?

Further data from the retrospective study showed that the most common reason for study failure was moderately differentiated by treatment type. Strategic decisions were the most common reason for failure in immunotherapy (n = 46 of 84; 54.8%) and targeted therapy trials (n = 17 of 62; 27.4%); recruitment was the most commonly cited reason for the failure of other studies.

Findings from a multivariable logistic regression analysis identified some independent factors that were predictive of early trial failure in HNSCC. Increased log-transformed enrollment was found to have a protective effect on study termination and withdrawal (OR, 0.36; 95% CI, 0.30-0.42). Industry-funded trials displayed a higher risk of termination compared with those that were funded by the government (OR, 2.84; 95% CI, 1.16-7.17). Each progression of trial phase increased the odds of termination (OR, 1.81; 95% CI, 1.35-2.45), and the inclusion of a procedure or surgery was a strong predictor of failure (OR, 1.98; 95% CI, 1.12-3.54). The study authors noted that funding from nongovernmental sources and inclusion of drug, device, biological/vaccine, or radiation were protective of study termination; however, the width of the 95% CI did not allow for precise estimates.

“Our findings help inform clinical investigators to consider risk factors for failure and protective factors based on the design constraints of their study,” the research team said. “Investigators conducting phase 1 trials, industry-sponsored trials, and immunotherapy and targeted therapy trials for HNSCC may benefit from conducting more rigorous feasibility assessments and exploring adaptive trial designs for further flexibility.”

The research team explained that their findings emphasize the need for new recruitment schema for studies that are at risk of failure due to poor recruitment, including later-phase trials, non–industry-sponsored trials, and trials investigating chemotherapy, radiation, chemoradiation, combination treatments, and supportive care. Moreover, studies that are at risk of operational failure could use safeguards such as stronger site selection and better data monitoring practices. For phase 1 studies specifically, the research team argued that more rigorous feasibility assessments and adaptive trial designs for further flexibility could improve the termination rates of phase 1, industry-sponsored, and immunotherapy and targeted therapy trials.

“More thorough clinical trial analyses for the head and neck cancer indication may help identify evidence-based inclusion criteria and study outcomes to help improve the likelihood of success and minimize the risk of termination/withdrawal,” the research team noted. “Further studies driven by collaborative team science between otolaryngologists, oncologists, and oral oncologists are needed to help address the unmet needs of patients with head and neck cancer.”

References

1. Huang JJ, Reznik AS, Sonis S, Franzmann EJ, Villa A. Clinical trial termination or withdrawal in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg. Published online January 2, 2026. doi:10.1001/jamaoto.2025.4766
2. Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049-3062. doi:10.1016/j.apsb.2022.02.002