Effectiveness issues – Population

1. Trial population mix differs from usual practice

Application of trial inclusion/exclusion criteria, together with other factors affecting recruitment, may mean that the trial population does not coincide with the population likely to be treated locally in usual practice. There may be differences in the distribution by age, gender, ethnicity, socio-economic factors, co-morbidities or other factors. Firstly, this is of concern if the intervention of interest has different efficacy across these factors. Secondly, even in the absence of such efficacy differences, the risk profile of the study population for the outcome of interest may differ from that of the population likely to be treated in usual practice. In this case there may be different levels of absolute effect (events averted etc.) associated with levels of trial-reported efficacy for the different populations.

2. Trial participants are at a different position in treatment pathway

‘Treatment pathway’ refers to the sequence of previous treatments received, based on patient selection criteria and response to previous therapies, often reflected in clinical guidelines. The position of patients in the treatment pathway drives the choice of appropriate comparator.

The position in the treatment pathway occupied by trial participants may differ from that which they would occupy in usual practice in the healthcare system of interest. For example, in usual practice the new medicine may be considered for use (only) after the disease progressed on two types of therapy, whereas trial participants may have experienced disease progression on just one. This assumes that the pathway has not changed during the course of the trial.

3. Trial population (usual care) differs from populations in other studies

Effectiveness results from previous or concurrent studies of comparator therapies (including usual care or standard of care) are potentially useful for planning new studies, and for inclusion in indirect comparisons or meta-analyses that include results for the new medicine of interest. However, the populations included in these studies may have different characteristics to the target population for the new medicine. Differences may be related to demographics, risk profile, place in the treatment pathway, concomitant care received or referral practices. These may be a result of secular changes in patient management since these data were reported. As a result there may be variations in effectiveness reported for usual care in such trials or non-randomised studies, which may present problems for trial design (for example, using expected event rates to calculate adequate study size) as well as for meta-analyses synthesising results from relevant trials.

4. Disease area is not well defined

The disease/indication may have an imprecise definition, and so there may be no well-established criteria for defining the population of interest, likely to receive the new intervention. A clinical code (ICD or other) may not yet have been established for the disease entity. Correspondingly there may be a lack of clinical guidelines, and usual care (or standard of care) may not be well established for the target population within an agreed treatment pathway. This may lead to uncertainty in applying trial results to the local context, as well as subsequent difficulties in setting up studies to monitor the usage and effectiveness of the medicine post-launch.