  The past few years have seen an increasing number of initiatives aimed at
integrating information generated outside of confirmatory randomised clinical
trials (RCTs) into drug development. However, data generated non-concurrently
and through observational studies can provide results that are difficult to
compare with randomised trial data. Moreover, the scientific questions these
data can serve to answer often remain vague. Our starting point is to use
clearly defined objectives for evidence generation, which are formulated
towards early discussion with health technology assessment (HTA) bodies and are
additional to regulatory requirements for authorisation of a new treatment. 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. These enabling designs facilitate estimation of
certain 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.
