Generating the right evidence at the right time: Principles of a new class of flexible augmented clinical trial designs.

To support informed decision making, clear descriptions of the beneficial and harmful effects of a treatment are needed by various stakeholders. The current paradigm is to generate evidence sequentially though different experiments. However, data generated later, perhaps through observational studies, can be difficult to compare with earlier randomised trial data, resulting in confusion in understanding and interpretation of treatment effects. Moreover, the scientific questions these later experiments can serve to answer often remain vague. We propose FACTIVE (Flexible Augmented Clinical Trial for Improved eVidence gEneration), a new class of study designs enabling flexible augmentation of confirmatory randomised controlled trials with concurrent and close-to-real-world elements. Our starting point is to use clearly defined objectives for evidence generation, which are formulated through early discussion with health technology assessment (HTA) bodies and are additional to regulatory requirements for authorisation of a new treatment. These enabling designs facilitate estimation of certain, well-defined treatment effects in the confirmatory part and other, complementary treatment effects in a concurrent real-world part. Each stakeholder should use the evidence that is relevant within their own decision-making framework. High quality data are generated under one single protocol and the use of randomisation ensures rigorous statistical inference and interpretation within and between the different parts of the experiment. Evidence for the decision-making of HTA bodies could be available earlier than is currently the case.