Abstract
This study evaluates a cross-section of interventional clinical trials registered on ClinicalTrials.gov with publicly available informed consent forms along with the proportion of trials that disclosed the possibility of trial termination.
Trial termination (the decision to end a trial earlier than planned) has been reported in 17.9% of cardiovascular trials and 16.0% of surgical trials.1,2 Although some trials are terminated for scientific reasons due to safety, efficacy, or futility, many trials are terminated due to inadequate participant enrollment or other nonscientific reasons.
Trials terminating for nonscientific reasons place participants at unnecessary risk without the promised benefit of creating generalizable knowledge. Given the frequency with which trial termination occurs, and the effect it may have on motivating factors for participation, prospective participants should be informed of the possibility of trial termination during the informed consent process.3
We evaluated a cross-section of interventional clinical trials registered on ClinicalTrials.gov with publicly available informed consent forms and assessed the proportion of trials that disclosed the possibility of trial termination.
Methods
We identified all interventional clinical trials enrolling adults with at least 1 trial site in the US; with any trial status listed; investigating a drug, biological product, or device; and with posted informed consent forms on ClinicalTrials.gov. The trials with a study start date between January 1, 2019, and March 12, 2022, were included. Informed consent forms were evaluated for any statement disclosing that a trial could be terminated early.
For trials that disclosed the possibility of early termination, we evaluated whether the discussion included (1) the possible reasons for trial termination; (2) participant provisions after trial termination; (3) the named parties with the authority to terminate the trial; (4) the likelihood of trial termination; and (5) the effect of trial termination on the social value of the trial (eg, its ability to produce generalizable knowledge that could benefit greater society). The determination of items 1 to 4 was based on regulatory guidance.4 All informed consent forms were independently assessed by 2 nonauthor coders with disagreements resolved by an author coder (N.H.).
The primary outcome and binomial 95% CI reflect the proportion of informed consent forms disclosing the possibility of trial termination. The proportion of trials addressing each of the 5 elements of a trial termination discussion was evaluated as detailed above. The data analyses were performed using R version 4.1.3 (R Foundation).
Results
Of 464 records identified, 249 trials met the inclusion criteria and were included in the analysis (Table). Almost 17% of the included trials were sponsored by industry. The majority of the trials had a status of completed (40.2%) or terminated (18.5%). The informed consent forms for the majority of the trials disclosed the possibility of trial termination (141 of 249 trials [56.6%; 95% CI, 50.2%-62.9%]). Interrater reliability for coding of the primary outcome was 0.95 using an unweighted Cohen κ.
Table. Trial Characteristics.
| Characteristics | Trials, No. (%) (N = 249) |
|---|---|
| Phase | |
| Not applicablea | 92 (36.9) |
| Early phase 1 or phase 1 | 29 (11.6) |
| Phase 1/2 or phase 2 | 74 (29.7) |
| Phase 2/3 or phase 3 | 32 (12.9) |
| Phase 4 | 22 (8.8) |
| Key funder typeb | |
| NIH or another federal agencyc | 86 (34.5) |
| Industryd | 42 (16.9) |
| Othere | 121 (48.6) |
| Recruitment status | |
| Active, not recruiting | 19 (7.6) |
| Completed | 100 (40.2) |
| Enrolling by invitation | 5 (2.0) |
| Not yet recruiting | 3 (1.2) |
| Recruiting | 73 (29.3) |
| Suspended | 1 (0.4) |
| Terminated | 46 (18.5) |
| Unknown status | 2 (0.8) |
| Study designf | |
| Multigroup | 176 (70.7) |
| Multisite | 72 (28.9) |
| Randomized | 158 (63.5) |
| Blindedg | 120 (48.2) |
Refers to trials without a phase defined by the US Food and Drug Administration; for example, trials of behavioral interventions.
Mutually exclusive categories.
The lead sponsor or collaborator was at least 1 of the National Institutes of Health (NIH) institutes or centers or another federal agency.
The lead sponsor or collaborator was not 1 of the NIH institutes or centers or another federal agency.
The lead sponsor or collaborator was not industry, not 1 of the NIH institutes or centers, and not another federal agency.
These are not mutually exclusive categories and the numbers do not sum to 249.
At least single-blinded.
Of the 141 trials with informed consent forms that discussed the possibility of trial termination, 130 (92.2%) identified the parties with the authority to terminate a trial, 6 (4.3%) provided information on participant provisions after termination of the trial, 3 (2.1%) listed possible reasons why a trial might terminate, and none addressed the likelihood of termination or the potential effect of trial termination on the social value of the trial.
Discussion
Despite the frequency with which early trial termination occurs, only 56.6% of informed consent forms acknowledged the possibility of trial termination. Early termination may affect participants in the following ways: it may interrupt treatment, affecting the prospect of direct benefit, and it may also prevent realization of the social value of the trial.
In certain circumstances, trial termination may have little material effect on the participants, whose immediate care remains the ethical responsibility of the research team. In all of these cases, transparency, which is a key function of informed consent,5 dictates that the possibility of trial termination should be disclosed at the outset so that participants are aware of its potential ramifications.
Conveying the effect on participants of possible trial termination will be challenging.6 Future research is required to evaluate how best to communicate this possibility and the effect disclosure may have on trial enrollment and trust in the research enterprise.
This study was limited by the small proportion of trials with publicly available informed consent forms on ClinicalTrials.gov, and the conclusions may not be representative of all registered trials.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
Data Sharing Statement
References
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Supplementary Materials
Data Sharing Statement