From the Guidelines
A clinical trial should be paused when there are significant safety concerns or efficacy issues that threaten participant welfare or compromise the study's scientific integrity, as evidenced by studies such as the ILLUMINATE trial 1 and the PALLAS trial 1, which were stopped early due to safety concerns. When considering pausing a clinical trial, it is essential to weigh the potential benefits against the risks, taking into account the severity of the condition being studied, the availability of alternative treatments, and the risk-benefit profile of the intervention being tested. Some key factors that may prompt a pause in a clinical trial include:
- Serious adverse events occurring at higher-than-expected rates
- Life-threatening side effects emerging
- Interim analyses revealing clear treatment futility or overwhelming efficacy, making it unethical to continue withholding treatment from the control group Data Safety Monitoring Boards (DSMBs) play a crucial role in making these decisions, using predetermined stopping rules established in the trial protocol, such as those outlined in the planned stopping boundaries for an event-driven trial 1. For instance, if a trial shows a significant increase in major bleeding events, as seen in the APPRAISE 2 trial 1, or a dramatic improvement in survival, as might be seen in a cancer treatment trial, the DSMB may recommend pausing the trial to protect participants and maintain scientific integrity. Ultimately, the decision to pause a clinical trial should be guided by a commitment to protecting participant welfare and ensuring the scientific validity of the study, as emphasized in ethical guidelines for clinical research 1.
From the Research
Reasons for Pausing a Clinical Trial
- A clinical trial should be paused due to safety concerns, such as evidence of harm 2, or efficacy issues, such as a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models 3.
- Other reasons for pausing a trial include evidence of futility, which occurs when a trial is unlikely to achieve its intended outcome 2.
Safety Concerns
- Certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues 3.
- Liver tests abnormalities can also be a safety concern, as seen with licensed antiviral drugs for COVID-19, such as remdesivir, molnupiravir, and ritonavir-boosted nirmatrelvir 4.
- Hepatotoxicity can be a problem in cancer chemotherapy, and liver function tests should be monitored when administering drugs with known hepatic toxicity 5.
Efficacy Issues
- Trials are more likely to stop due to a lack of efficacy if there is no strong genetic evidence from human populations or genetically modified animal models to support the therapeutic hypothesis 3.
- The use of surrogate, composite, and subjective endpoints can make it difficult to interpret trial outcomes and can undermine the translation of research into practice and policy 6.
- Trial outcomes should be developed with patients in mind and reported completely, transparently, and competently to ensure that the results are relevant and useful 6.