Although the usual care (or standard of care) medicine for the healthcare system is included as a comparator in the trial, its administration in the study (for example, dose, dose titration/escalation, frequency, route of administration, monitoring) may differ from usual practice in the country of interest. This may raise concerns about the transferability of study results to (local) usual practice. In some cases the clinical background and skill level of the administering clinicians may be important.
Development stage: Mid
Administration of therapy is inconsistent with usual practice
The administration of the study medicine in trials (for example, dose, dose titration/escalation, frequency, route of administration, monitoring) may differ from the schedule that is likely to be used in clinical practice. This is perhaps more likely if the new therapy is added to current usual care, or if the treatment itself may be intentionally misused by patients if its administration is not under strict control (for example, opioids in pain relief). In some cases the clinical background and skill level of the administering clinicians may be important.
Trial settings and sites do not reflect usual clinical practice
In multi-national studies the general level of care (concomitant therapies, access to technologies, patent support programmes) received by trial participants in some healthcare systems or study sites may differ from usual practice in the healthcare system of interest. This may have implications for the generalisability of the effectiveness results to that system. Recruitment of study participants may require a specific diagnostic activity that is currently not part of usual practice. Clinicians’ or participants’ willingness to participate or complete the trial may not be independent of factors such as adherence or underlying risk, which may be associated with effectiveness. This may be important when considering the applicability of results from studies in highly-resourced healthcare systems such as US, with increased access to sophisticated diagnostic and monitoring services as well as high-intensity care, to local populations where such services may not be available. If the effect of the medicine itself cannot be isolated from trial setting, then the combination of setting and intervention may need to be considered more broadly as an intervention strategy in its own right.
Adherence in study differs from usual practice
Outcomes reported in trials are usually for study participants at a high level of adherence to the study medicine and comparators. However, in usual practice lower levels of adherence are expected, potentially with different levels of adherence for different therapy options resulting from differences in side effects or methods of administration. In the absence of real-world evidence, an understanding of the relationship between effectiveness and adherence is required to project estimates of effectiveness in usual practice (with sub-optimal adherence) from efficacy reported in trials. However, the relationship (often non-linear) may be difficult to predict. Having real-world data on adherence alone is insufficient to estimate effectiveness.
Stopping rules for therapy are unclear
The administration of the study medicine in trials (for example, dose, dose titration/escalation, frequency, route of administration, monitoring) may differ from the schedule that is likely to be used in clinical practice. This is perhaps more likely if the new therapy is added to current usual care, or if the treatment itself may be intentionally misused by patients if its administration is not under strict control (for example, opioids in pain relief). In some cases the clinical background and skill level of the administering clinicians may be important.
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.
Other study design choices may limit generalisability
In multi-national studies the general level of care (concomitant therapies, access to technologies, patent support programmes) received by trial participants in some healthcare systems or study sites may differ from usual practice in the healthcare system of interest. This may have implications for the generalisability of the effectiveness results to that system. Recruitment of study participants may require a specific diagnostic activity that is currently not part of usual practice. Clinicians’ or participants’ willingness to participate or complete the trial may not be independent of factors such as adherence or underlying risk, which may be associated with effectiveness. This may be important when considering the applicability of results from studies in highly-resourced healthcare systems such as US, with increased access to sophisticated diagnostic and monitoring services as well as high-intensity care, to local populations where such services may not be available. If the effect of the medicine itself cannot be isolated from trial setting, then the combination of setting and intervention may need to be considered more broadly as an intervention strategy in its own right.
Trial treatment pathway is not generalisable to usual practice
‘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. Assessment of the position in the treatment pathway drives the definition of the treatment population and choice of appropriate comparator. This pathway may have changed during the course of the trial if a new medicine has been approved or new clinical guidelines have been implemented locally. In some cases, the introduction of the medicine of interest will itself alter the treatment pathway. Alternatively there may not yet be an established treatment pathway or sequencing, and as a result there may be variations across countries or health centres within countries.
Definition of trial outcome is inconsistent across studies or with usual practice
Trial results may be difficult to interpret because of different (possibly inconsistent) efficacy results across the pivotal studies. This may be due to differences in the trial populations associated with differences in efficacy across important sub-populations.
Results for an individual trial may vary in magnitude and/or direction for different outcomes, making interpretation less straightforward, for example when reviewing results for individual components of composite endpoints.
There is uncertainty in reported trial outcomes
Trial results may be difficult to interpret because of large uncertainty (wide confidence intervals) in the outcome measures. Trials may not have been powered specifically to detect differences in patient-relevant endpoints such as health-related quality of life. In some healthcare systems, secondary and tertiary outcomes may be considered to be lower quality evidence. High levels of uncertainty may be reported if there are lower rates of the outcome event than expected. Results for subgroups of importance to the health system of interest will have greater uncertainty, and in some cases may not have been reported.
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.
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.
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.
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.