Premature Clinical Trial Discontinuation in the Era of Immune Checkpoint Inhibitors

Abstract

Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. This study assessed factors of early terminated/withdrawn oncology trials, focusing on trials with immune checkpoint inhibitors (ICI), and found that poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in immune checkpoint inhibitor trials compared to other trials. The discussion herein is focused on measures taken by the National Cancer Institute and other institutions to improve clinical trial accrual and prevent premature clinical trial discontinuation.

Unfinished business: Terminated cancer trials and the relevance of treatment intent, sponsors and intervention types

“…More recently, Khunger et al published a similar analysis, which focused on immunotherapy trials compared to other oncology drug trials. The authors did not find a significantly different withdrawal or termination rate of immunotherapy trials compared to all other systemic cancer therapy studies; in line with the previous data, the authors confirmed lack of accrual as the major reason for trial termination 4 …”

“…We did not observe a general correlation of symptom-control interventions with completion or termination of trials, to the contrary, symptomcontrol interventions performed in a curative setting were associated with an increased chance of success in the multivariate model; again, in the univariate analyses, this association was only observed in nonindustry-sponsored trials. Trials conducted exclusively in the United States were at an increased risk of termination in the multivariate models; however, this observation may be due to a selection bias: It is likely that almost all Phase 3 US oncology trials are registered with ClinicalTrials.gov while trials conducted at other locations are primarily registered locally and those additionally registered with ClinicalTrials.gov might be structurally different from a random sample of (only) locally registered trials.It must be emphasized that the overall model performance of the predictive models was relatively poor; that is, although the models show that some factors are predictors of trial termination, an accurate prediction of trial termination is not possible with the analyzed combination of factors.Neither the aforementioned positive 3 nor the negative4 association of industry-sponsoring with trial termination was confirmed in our data set. We observed a similar distribution of completed and terminated trials irrespective of sponsorship (absolute difference: 1.8%).Trial recruitment rates, on the other hand, were considerably faster (>3 times) in industry-sponsored trials; this association was also observed in a multivariate model.…”

“…In their analysis about terminated cancer trials registered between 2005 and 2011, which included only about 20% late‐stage trials, Stensland et al identified industry‐sponsoring as a risk factor for premature discontinuation of trials 3 . Khunger et al, who reported on a data set of studies registered between 2011 and 2015, also included early‐stage trials with only a minority of late‐stage studies (10%); interestingly, the authors could not confirm industry‐sponsorship as a risk factor for early termination but rather found that trials sponsored by individual institutions were more likely to be discontinued than industry‐sponsored trials 4 …”

“…interestingly, the authors could not confirm industry-sponsorship as a risk factor for early termination but rather found that trials sponsored by individual institutions were more likely to be discontinued than industry-sponsored trials. 4 Our analysis is conceptually different from aforementioned studies because we analyzed a more homogeneous dataset by excluding all early-stage trials; furthermore, we excluded ongoing trials and compared only terminated and permanently suspended trials with completed trials, as a control group. This approach allowed us to perform a detailed study-by-study evaluation of each trial with regard to treatment intent and treatment setting, that is, palliative or curative in addition to intervention type which was also analyzed by aforementioned studies but slightly modified in our analysis to account for com- F I G U R E 4 A, Terminated studies compared to completed studies in nonindustry-sponsored trials.…”

“…The authors did not find a significantly different withdrawal or termination rate of immunotherapy trials compared to all other systemic cancer therapy studies; in line with the previous data, the authors confirmed lack of accrual as the major reason for trial termination. 4 Another aspect of the clinical trials landscape is the increasing percentage of industry-sponsored trials. Industry sponsorship has increased from 4% in 1975 to 57% in 2004.…”