Importance of RWD Analyses
DBPC trials are considered the gold-standard for evaluating efficacy since they prevent systematic bias in allocation of treatment and are demanded by regulatory authorities for gaining marketing authorizations. Nevertheless, there are some limitations because of restricted study durations, small numbers of patients, controlled settings and the placebo effect (10,11,27,28). The missing external validity leads to a low generalizability because RCTs are performed in conditions very different from daily practice (28): patients in daily practice are more often diverse especially concerning age, sex or concomitant diseases which may have an impact on treatment efficacy (27,29). In contrast, RWD have high generalizability since they investigate effectiveness under routine circumstances (28) and they offer the option for long-term evaluations. The data can be analysed within a short time, in patient groups that are usually not included in RCTs (e. g. patients with comorbidities), in different age groups and with a manageable investment.
Some signals or effects may even show up only in RWD studies. In a structured literature review, Elliot et al. compared hypoglycemia event rates/patient/year in type 1 diabetes mellitus (T1DM) and insulin-treated type 2 diabetes mellitus (T2DM). In both patient groups, higher rates of hypoglycemia were observed in real-world settings compared to clinical trial settings, especially in patients with T1DM. The authors concluded that RCTs are likely to underestimate the burden of hypoglycemia in clinical practice (30). One of the studies included here showed that AIT treatment was associated with a significantly reduced likelihood of developing pneumonia and receiving antibiotics prescriptions compared to the Non-AIT control group (25). Due to the small proportion of patients suffering from pneumonia (1.4% in the AIT group, 2.0% in the Non-AIT control group) such significant differences would probably not show up in any RCT.
It may not be expected that the outcomes of RWD and RCT analyses are invariably congruent. One reason for this is the so-called ‚efficacy-effectiveness gap‘, which means that the effectiveness in clinical practice is generally reduced compared to the efficacy shown in RCTs by transfer and implementation loss, e.g. delivery of care, adherence to treatment, and time between treatment and assessment of the outcome (31,32). Nevertheless, consistency between RWD and RCT data were already shown for indications like metastatic renal cell carcinoma when treated with the tyrosine kinase inhibitor sunitinib or the use of antipsychotics in schizophrenia (33,34).
RWD represent non-selected large patient groups therefore complementing but not replacing results from RCTs (10). There is increasing interest of regulatory authorities to evaluate the options that RWE may offer, e.g. with regard to ‘identify areas of highest unmet needs where real world evidence (RWE) can supplement clinical trial data in regulatory decision making’ (EMA/705364/2021; (35) (36). Since the methodological prerequisites are not fixed yet it probably will take some more years until RWD may be supportive in granting marketing authorizations for AIT products. Until now, the terms ‘RWD’ or ‘RWE’ are not used in the same way by different authorities (see Table S7 in supplementary information).