Major protocol violations/deviations
Major deviation was defined as having been treated according to the other treatment arm. Patients not receiving 1 of the protocol treatments were excluded from safety analyses. Otherwise, patients were not excluded from analyses due to post-randomisation deviations.
The reported rates of any protocol deviations were high (93.9%) in both parts of the Phase II study, with 10.6% in Part 1 and 10.1% in the control considered ‘clinically significant’ deviations; most of these were breaches of the inclusion/exclusion criteria such as the menopausal status of 4 patients not being confirmed. Incorrect stratification factors being used at the time of randomisation led to some small imbalances in prognostic factors eg higher rates of visceral disease in the letrozole alone arm.
Comment: The impact of the frequent and wide-ranging nature of these protocol deviations (including inclusion/exclusion criteria, randomisation, deviations from the conduct of the study and study assessments) on the outcome is difficult to assess, especially when not provided by treatment allocation and the definition of the sponsor’s phrase ‘clinically significant’ could not be found. However, following a detailed review of protocol deviations, it is noted that the FDA clinical reviewers of Study 1003 concluded that these were unlikely to affect the efficacy outcomes significantly (FDA clinical review report, Study 1003 NDA).
The median age was 62.5 years (range: 41 to 89 years) and 64.0 years (range: 38 to 84 years) in the palbociclib plus letrozole arm and the letrozole alone arm, respectively (see Table 9).
Comment: The baseline demographics were reasonably balanced between the arms, particularly given the small size of the study. The study population was mostly White and no men were included. Of relevance to the Australian population, is noted that studies in Asian patients are underway which will likely determine whether there are any clinically significant differences.
Table 9: Study A5481003 Demographic characteristics for Phase II ITT population