10 September 2020 - The recently published PBAC Public Summary Document for AbbVie’s JAK inhibitor Rinvoq reveals a very interesting development.

The PBAC recommended the PBS (Authority required) listing of upadacitinib monohydrate for the treatment of patients with rheumatoid arthritis.

The Committee considered the nominated comparators of baricitinib and adalimumab were reasonable; however, noted any of the biological disease modifying anti-rheumatic drugs currently listed on the PBS for rheumatoid arthritis were relevant alternative therapies.

The PBAC considered the claims that upadacitinib monohydrate is non-inferior to baricitinib in terms of effectiveness and safety and non-inferior in terms of safety compared to adalimumab, were adequately supported by the clinical evidence presented in the submission. The PBAC considered the claim of superior effectiveness versus adalimumab was not fully supported by the evidence. The PBAC noted no evidence demonstrating superiority against any of the other alternative therapies was provided.

The Committee noted that the claim of superior effectiveness versus adalimumab was based on ACR50 results in the SELECT-COMPARE trial meeting the pre-specified tests for non-inferiority and then superiority of upadacitinib monohydrate versus adalimumab. That is, the lower bound of the 95% confidence interval for the risk difference was larger than the nominated non-inferiority margin of -10%, and then larger than 0% (i.e. statistically significant) in accordance with the sequential testing procedure.

The PBAC recalled it had previously rejected a superior efficacy claim for baricitinib versus adalimumab based on similar evidence, and suggested using the inverse of the non-inferiority margin to establish superiority rather than statistical significance (Baricitinib PSD, July 2017). The PBAC also noted the pre-PBAC response of AbbVie stated that upadacitinib monohydrate meets the requirements for statistical superiority as defined by global statistical norms through the ICH-E9 guidelines EMA guidelines and FDA guidelines.

The Committee noted these were regulatory guidelines focused on statistical superiority and not necessarily relevant to the assessment of clinical superiority. The PBAC reaffirmed its view that upadacitinib monohydrate failed to demonstrate clinical superiority based on the inverse of the non-inferiority margin, and therefore, considered that the claim of superior efficacy over adalimumab was not adequately supported.

It is interesting to find the PBAC has used a novel statistical method to determine the acceptability of a clinical claim. The method is not well established and appears to have been used ad hoc.

AbbVie is challenging the use of the "inverse of the non-inferiority margin" method. It would appear as though the challenge is a matter of principle, rather than one of price.

Future issues of MAESTrO Daily will explore this issue in further detail.

Read PBAC Public Summary Document for upadacitinib monohydrate