Early Termination of a Clinical Trial23-12-2021
Clinical trials establish strict protocols, with detailed information on the number of visits, treatments, and procedures that must be followed thoroughly, with no deviations. A clinical trial finishes when the last patient enrolled completes all their visits and follow-ups. However, a clinical trial may be terminated early for different reasons.
Reasons for early termination of a clinical trial should focus on the effectiveness and safety of the study interventions. In addition to the sponsor, who is the responsible party for making this type of decision, large clinical trials have a safety and efficacy Independent Data Monitoring Committee (IDMC). This Committee confidentially manages and analyzes study results as they are being collected, in what are known as interim analyses.
Following each interim analysis, a decision must be made regarding whether the clinical trial should continue, be modified, or be terminated early. In the event of deciding to terminate the trial early, the sponsor should promptly communicate it to all participating investigators, site managers, to the Drug Research Ethics Committee (CEIm, as per the Spanish acronym) that approved the trial and to the regulatory agencies, such as the Spanish Agency for Medicine and Health Products (AEMPS, as per the Spanish acronym), if the trial is only conducted in Spain, and to international agencies, such as the European Medicines Agency (EMA), in the case of Europe, or the Food and Drug Administration (FDA), in the case of the United States. Moreover, the reasons for that decision must be explained.
Reasons for early terminating of a clinical trial
- Loss of the strategic interest because the market potential is insufficient, new drugs have been approved for the same indication, or because a positioning for other indications is being pursued.
- Logistics issues for being unable to recruit the expected number of subjects. It is important to publish this type of trials indicating problems observed and the causes leading to early termination, since they can help other investigators avoid the same problems and repeat the same mistakes.
- The benefit of the drug is proven early, which would mean that it is unethical to continue the trial with control patients, especially those treated with placebo. The main issue with early termination is that of considering that some results are sound when they are not. This may reduce the scientific validity of the trial and increase the chance of obtaining false results, increasing differences with other treatments. In addition, prompt disclosure of results may influence the clinical practice and result in therapeutic strategies persisting over time when they are not the most appropriate ones.
- The drug's lack of efficacy is proven early for failure to obtain the expected benefit. Treatment does not lead to an equal or better result than the treatment against which it is compared.
- Be shown prematurely (in an interim analysis) that the drug is harmful, resulting in a risk for patients enrolled in the trial.
To conclude, criteria to discontinue a clinical trial early must be very strict at the time of determining the scope of the effect. This situation can only be found with a cumulative number of events higher than 200. On the other hand, it should also be considered that both the adjustment and the accuracy of the estimate (or p value) —based on the number of interim data analyses— may lead to an understanding of the true effect of treatment in clinical trials that are terminated early.