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).