Limitations
An evidence-based approach to interpretation of clinical trial data
turns first to the hierarchy of evidence. RCTs are higher on the
hierarchy than observational studies because randomization provides
powerful protection against known and unknown confounders that
observational studies do not. Given that the COMPASS findings were from
an RCT and found no increase in all-cause mortality and the
observational studies found an increase in all-cause mortality with PPI
use, the hierarchy of evidence points to the interpretation that the RCT
findings should be accepted and the observational findings understood as
being most likely explained by an unidentified confounder31.
Pharmacovigilance – “the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects
or any other drug-related problem”32. challenges the
use of the hierarchy of evidence for evaluating drug risk:
[N]one of the methods … (experimental data, clinical trials,
spontaneous notifications, case–control studies, cohort studies and
data mining) should be considered as definitive for evaluating drug
risk. It is only the convergence of proofs which allows final
conclusions and decisions in pharmacovigilance. Thus, the notion of
‘levels of evidence’, widely used for evaluating drug efficacy, cannot
be applied in the field of [Adverse Drug Reactions] ADRs; all
methods are of interest for evaluation of ADRs 33.
Insisting on RCT evidence for fatal and serious adverse events from
medication use in real-life populations contravenes modern standards in
pharmacovigilance that are more directly applicable to the evaluation of
the serious adverse events associated with medications.