Trial comparators do not include current usual care or standard of care

Current usual care (or standard of care) for the healthcare system of interest is not included as a comparator in the clinical trial. This may be because there is wide variation in usual care across healthcare systems, so that not all options can be included in a single study. A ’usual care’ medicine in the country of interest may not be licensed or reimbursed, or it may not be recommended for use (for example, in clinical guidelines) in some study countries, preventing its inclusion in the trial. In some cases a placebo-controlled trial may have been required to support regulatory approval, for example to resolve safety concerns, which might preclude the inclusion of usual care as a comparator in the trial. It is possible that more than one usual care comparator is relevant for different segments of the target population, for example if a new diagnostic paradigm is involved.

Any comparison with usual care based on clinical trial data will therefore need to rely on an indirect comparison, for example a network meta-analysis based on an evidence network of results from all trials in populations with the disease of interest. Such analyses depend on statistical modelling assumptions (mostly concerning heterogeneity of the results across the source trials) as well as similarity in the design of the source trials (for example, study durations, study populations and definitions of health outcomes). Results of such meta-analyses may be associated with high levels of uncertainty. They are viewed with caution by some decision-makers because they are quite new (not yet fully ‘tried and tested’), are quire complex (loss of transparency) and are not yet widely understood.