Why We Fail: An Analysis of Terminated Interventional Clinical Trials in Lymphoma

Introduction:

Clinical trials serve as the cornerstone for advancing therapeutic and clinical strategies in Lymphoma. Learning from prematurely terminated trials provides valuable insights for researchers and drug developers. This study analyses interventional clinical trials in lymphoma terminated between 2010 and 2023, aiming to identify common factors contributing to their failure and improve future research in Lymphoma.

Methods

The study identified clinical trials in Lymphoma registered in the US between 01/01/2010, and 01/07/2023, using the InovaSight platform. The analysis included trials investigating drugs in phases I-III with at least one recruited patient. Phase 4 studies, early access programs, and trials examining medical devices were excluded, as were trials terminated early due to positive efficacy signals.

Natural language processing (NLP) & classification algorithms were used to categorize trials into distinct phases of clinical development and were also applied to identify reasons for trial termination from official registrations and relevant publications. These reasons were then characterized using the InovaSight trial ontology for thematic analysis.

Enriching features, including mechanism of action information, design characteristics, target enrolment, and inclusion criteria, were generated and linked for each eligible trial.

The analysis was conducted using the InovaSight drug development platform, which employs responsible artificial intelligence to expedite the development of novel therapeutics for haematological malignancies.

Results:

A total of 306 trials met the inclusion criteria, with phase II trials being most frequently withdrawn (49.3%), followed by phase I (42.5%) and phase III (8.2%). The trials spanned from 2010-01-31 to 2021-12-15. Among terminated studies, single-arm trials were most frequent (64%), followed by two-armed designs (21.2%) and three or more arms (14.7%). A concentration of mechanisms of action were observed across all phases (further described in poster). Reasons for early termination included enrolment issues, sponsor decisions, lack of efficacy, safety concerns, funding withdrawal, investigator-related issues, study irrelevance, drug supply problems, COVID-19, and unspecified reasons. The most common reason for early termination was enrolment issues in Phase I and Phase II studies, and sponsor decisions in Phase III studies. Detailed results are presented in Figure 1.

Discussion:

Our analysis identified a total of 306 trials that met the inclusion criteria, encompassing different phases of clinical development. Interestingly, phase II trials were the most frequently withdrawn, followed by phase I and phase III trials. This observation suggests that a considerable number of trials face challenges during the intermediate stages of development, which could be attributed to various factors such as safety concerns, lack of efficacy, or financial constraints.

Our analysis revealed a concentration of similar mechanisms of action across all trial phases. This finding suggests that certain therapeutic areas or drug targets may be more prone to early termination. Exploring the underlying reasons for this pattern could provide valuable insights for future trial planning and design (This is further elucidated in the full presentation).

Among the various reasons for early termination, enrolment issues emerged as the most common factor in both Phase I and Phase II studies. This highlights the critical need for in depth and principled approaches to study feasibility assessment routed in an evidence-based methodology. In contrast, sponsor decisions were the leading cause of termination in Phase III trials. This finding suggests that late-stage trials are more susceptible to decisions made by the trial sponsors, which could be influenced by factors such as financial considerations or market dynamics.

The results underscore the importance of careful trial planning, patient recruitment strategies, and effective collaboration between sponsors, investigators, and regulatory bodies. Understanding the challenges and factors contributing to trial termination can aid in optimizing future trial designs, mitigating risks, and improving the efficiency of drug development processes.