1. Introduction

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There are many different types of decision that may need to be made once a clinical trial has begun. Some are routine decisions in managing a trial, but especially in case of safety issues, some decisions may have a major impact on the conduct of the trial, and could even result in the termination of the trial.

These decisions can also result in the modification of the study protocol, e.g. the trial rationale, procedural aspects, inclusion and exclusion criteria, medication and dose to be used, as well as many other details.

There are many different issues that may arise during the conduct of the trial that may necessitate immediate decision-making, such as premature trial termination. Such issues may be related to the emergence of new scientific evidence, as the trial progresses, e.g. interim trial results may give an indication on whether an intervention is beneficial or not. Trial data, and their interim analysis, often necessitate a reassessment of the scientific validity of the trial, along with an examination of what is clinically meaningful and ethically sound. This reassessment may result in the modification or termination of the trial, when evidence arises that the original assessment of benefit-risk to the patient is no longer favourable, or when the beneficial effect is so evident that it is ethically unsound not to give the treatment to all the patients.

This requires continuous observation of the clinical trial participants and a general oversight of the study conduct, which is ensured by trial monitoring, implemented and maintained by the sponsor. Monitoring ensures that the rights and overall wellbeing of the patients are safeguarded, including the setup of reporting processes that indicate if there is a serious safety matter requiring immediate attention, for example, an unexpected serious safety signal.

A safety signal, according to the Council for International Organizations of Medical Sciences (CIOMS), is information that arises during the trial suggestive of a causal association between the intervention (e.g. the medicinal product being tested) and an event or set of related events, either adverse or beneficial, which is judged to be sufficient to justify further action.