Elucidating Conditions for Trial Termination in Head and Neck Studies

Foregrounded by high clinical trial failures in the head and neck squamous cell carcinoma (HNSCC) field, in a written correspondence, CancerNetwork® spoke with investigators of a clinical trial published in JAMA Otolaryngology – Head & Neck Surgery about their study investigating this trend.¹

Among those interviewed were Elizabeth J. Franzmann, MD, a surgical oncologist and professor in the Department of Otolaryngology-Head and Neck Surgery in the Division of Head & Neck Surgery in the Miller School of Medicine of the University of Miami, and 2 of her graduate students, Janice J. Huang and Alex S. Reznik. Collectively, they contributed their insights into the state of clinical trials for this disease state.

In the collaborative interview, the group established that most clinical trial failures are strategic, with the majority of phase 1, industry-sponsored, and immune/targeted therapy trials subject to this type of early termination. Moreover, recruitment challenges emerged as another leading cause for trial termination, with these types of failures encompassing many later-phase, non-industry–sponsored trials.

Next, they highlighted potential means to mitigate the frequency of these failures, which included measures aimed at bolstering trial enrollment: easing back restrictive inclusion criteria and the incorporation of safeguards to minimize the risk of operational failures. Finally, they discussed their insights regarding recent advances with the potential to transform practice in this field and emphasized a need for collaborative science based on the findings of their study.

CancerNetwork: What was the background behind the JAMA manuscript, and what were its objectives?

There is robust clinical trial activity for head and neck cancer, however, a significant portion of trials prematurely end in early termination (termination/withdrawal). Classically, when we speak about clinical trial failures, we equate a failure to not reaching a primary end point or not reaching FDA approval. This is especially relevant to the common statistic that 90% of drugs fail clinical drug development.² However, we sought out to focus on the understudied and significant portion of trials that are terminated and withdrawn - these trials do not reach the finish line and therefore represent a significant loss of resources and potentially beneficial clinical therapies.

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.

What were the study’s findings?

We identified 346 trial failures for the head and neck squamous cell carcinoma [HNSCC] indication. This was a comprehensive cohort of HNSCC failures. Case-control analysis identified significant risk factors for failure. First, we identified the leading reason for failure in the early-terminated trial group were strategic decisions - these are non-scientific sponsor-driven decisions to end the trial prematurely. Second, we identified that strategic decisions were more frequently the reason for failure in phase 1, industry-sponsored, and trials investigating immunotherapy and targeted therapy.

In addition, we found that poor recruitment was a more common reason for failure in later phase trials, non-industry-sponsored trials, and trials investigating chemotherapy, radiation, chemoradiation, combination treatments, and supportive care. This is important for the field because it represents data that could help inform the design of future clinical trials to try to avoid these pitfalls. Our study also identified an increasing rate of trial termination/withdrawal. A key protective factor was increased log-transformed actual enrollment, and we found that industry funding is a risk factor for trial termination/withdrawal.

How can the field rectify the frequency of trial failures and address the characteristics associated with these incidences?

There is significant heterogeneity in the design of HNSCC clinical trials (like many other indications). For head and neck, overly restrictive eligibility criteria may be one explanation for the trial failures attributed to poor recruitment, for example. New recruitment schemes and increased access to clinical trials may help address these challenges. To add, it is possible to incorporate safeguards to reduce the frequency of operational failures through stronger site selection, better data monitoring practices, and other methodological considerations described in our study.

How does the rising rate of trial failures impact the ability to provide evidence-based counseling to patients regarding the potential long-term adverse effects of novel therapies compared with current standard-of-care protocols?

Terminated and withdrawn trials often do not publish their safety and efficacy data in contrast to long-term safety and efficacy data from landmark clinical trials that resulted in the standard of care. Thus, trial failures increase the uncertainty during patient counseling and require close dialogue between clinicians, caretakers, and patients due to constraints in the available evidence.

How can multidisciplinary tumor boards better differentiate between therapies or trials that failed because of "strategic" reasons vs those that lacked clinical merit when considering future treatment pathways?

In our study, we defined strategic decisions as a sponsor decision unrelated to scientific concerns such as safety or efficacy. Other non-clinical reasons for failure include funding withdrawal and operational failures (such as regulatory issues, delays, principal investigator relocation).

In contrast, reasons for failure that are related to the properties of the intervention are poor safety and poor efficacy.

The reasons for failure are not always publicly available on ClinicalTrials.gov. However, several clues that can help pinpoint to the reasons for failure. First, based on our analysis, we show that industry-sponsored trials are more likely to fail due to strategic decisions, compared with academic trials which are more likely to fail because of enrollment challenges. Second, trial phase also can help stratify the risk of failure and the reasons for failure.

More broadly, the multidisciplinary expertise of tumor boards is especially well positioned to evaluate whether trial failure occurs because of poor clinical efficacy and/or safety signals, or a methodological error. These boards draw on experiences of many individuals within cross-cutting specialties whose collective experience includes running clinical trials, national meeting participation, and involvement in cooperative groups which can often shed light on the reasons for failure and how to design better trials in the future.

What recent developments in head and neck cancer surgery do you believe might have a profound impact on practice over the next year?

One example is transoral robotic surgery, which is a minimally invasive surgical procedure for the treatment of HNC. The method allows for efficient removal of the tumor site and affords treatment de-escalation, which has been shown to improve patient outcomes especially in HPV-negative head and neck tumors.

Is there anything else you would like to touch upon that we might not have covered in this discussion?

Our multi-institutional study team demonstrates the importance of collaborative science, especially between members of otolaryngology and oral oncology, which can further help support effective therapeutic development for our patients with HNSCC.

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 Pharma Sin B. 2022;12(7):3049-3062. doi:10.1016/j.apsb.2022.02.002