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.