For those funding, approving or advising on clinical trials and other evidence generation activities, there are different stages of medicine development when different issues may be relevant. For the purposes of this RWE Navigator, we describe these stages as Early, Mid, and Late.
See the figure and further descriptions of these stages below.
Early (strategy: programme planning)
Conventionally, a full clinical development plan for a new medicine is set out (or refined) towards the end of the phase 2a (proof of concept) study, which is usually a relatively small randomised controlled trial (RCT) in participants with the disease of interest.
At this stage, perhaps 5 years from launch, the design of larger dose-ranging (phase 2b) and confirmatory (phase 3) studies are planned, along with other studies (for example, in children) and likely timelines for regulatory submissions. An outline strategy and plan for generating evidence for reimbursement may be initiated, which should include an understanding of drivers of effectiveness and any likely gap between efficacy (measured in trials) and effectiveness (required by decision makers) (the 'efficacy-effectiveness gap' - seebackground of the efficacy-effectiveness gap).
The potential role of real-world evidence (RWE) to help address an efficacy-effectiveness gap can be considered at this stage, especially if this may impact on the phase 2b or 3 RCT designs.
Scientific advice processes are also available for consultation with regulatory or health technology assessment (HTA) agencies, which may be especially valuable if adaptive pathways are being considered (see key initiatives).
Mid (operational: designing and executing studies)
This operational phase includes design and execution of phase 2b and 3 studies.
Phase 3 studies represent a major investment decision for pharmaceutical research and development (R&D). These studies need to be optimised to provide relevant data on efficacy and safety for regulators, and where possible, to enable estimates of relative effectiveness to be derived for reimbursement or health technology assessment (HTA). Analyses using real-world data (RWD) may help to optimise the study design.
At this stage, consideration should be given to introducing more pragmatic elements into the trial (to increase generalisability) or undertaking a supplementary (phase 3b) study to generate data on effectiveness that the phase 3 randomised controlled trial (RCT) cannot provide.
Scientific advice with regulatory or HTA agencies is also available at this stage. However, the benefits of scientific advice are greater if it is sought before clinical development plans have been finalised.
The design of post-launch studies and any managed access schemes (coverage with evidence development) that a pharmaceutical company may wish to explore are also considered at this stage.
Late (submission: regulatory approval and reimbursement)
At this stage, the main evidence base has been created, from which submissions for regulatory approval (marketing authorisation) and then reimbursement will be constructed.
Along with results from primary real-world evidence (RWE) studies, real-world data (RWD) may be used in combination with trial results to meet the needs of decision makers (i.e. through re-analysis or predictive modelling). In addition, evidence syntheses may be expanded using the results of RWE studies.
Plans for further RWE studies may also be finalised at this stage. These may be in response to requirements set out by regulatory or reimbursement agencies.