Objective:

Pivotal studies to approve new medicines often do not use the most appropriate comparator. The objective is to quantify this problem by analysing the Therapeutic Positioning Reports (IPT for its acronym in Spanish) published by the Spanish Health Ministry.

Methods:

The comparator was classified into six categories, based on the appropriateness of the treatment, i.e. whether it matched the standard of treatment when authorised: A-"initially adequate" (at the start of the study), B-"no comparator for ethical reasons", C-"no comparator -excluding B-", D-"inadequate" and E-"partially suboptimal" (when it was standard for part of the included patients but not for all of them).

The primary endpoint was the proportion of new drugs/indications with sufficient (categories A, B and C) or poor comparator (the rest). Information on comparators and standard treatment was extracted from the IPT.

Results:

We randomly analysed 186 IPTs with new drugs or indications, published between 2013 and March 2022. Comparability was assessed as sufficient in 73.7% (95%CI 66.9-79.5) of cases. The remaining 26.3% (95%CI 20.5-33.1) had poor comparisons in the pivotal trial, either due to inadequate comparator (11.3%), partially suboptimal (5.4%) or absence of a comparative study excluding ethical justification (9.7%).

Conclusions:

Approximately one in four new medicines or indications lacks sufficient comparability at the time of entry into clinical practice. The proportion has not improved over the last 10 years. Regulatory agencies need to be more stringent in comparator selection for pivotal clinical trials, for ethical and health reasons.

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