eBook: The role of RWE in regulatory approvals. Download here.

FDA Decision Alerts October 28, 2020

CDER-Approved sNDA for IBRANCE® (palbociclib)

Nick Honig and Michelle Skornicki
Contributing writers, Aetion

On April 4, 2019, the FDA granted a label expansion to Pfizer’s IBRANCE® (palbociclib) “for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)­ negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or fulvestrant in patients with disease progression following endocrine therapy.”

Key findings from the FDA’s Multi-Discipline Review:

The FDA based the label expansion on its previous approvals of palbociclib. In its application package, the applicant submitted updated results of a phase 3 trial, PALOMA-2 (NCT01740427; n=666), to demonstrate palbociclib’s (with letrozole) efficacy in women with previously untreated HR-positive, HER2-negative advanced or metastatic breast cancer (MBC). Accordingly, PALOMA-2 provided substantial evidence of efficacy for the label expansion. The applicant also submitted two RWE studies to support the use of palbociclib in male breast cancer patients, and postmarketing data to support palbociclib’s safety profile.

Intent of the RWE studies
Flatiron study: Since males diagnosed with breast cancer were ineligible for previous palbociclib studies, the applicant submitted an RWE study to provide data supporting the use of palbociclib combined with endocrine therapy.

IQVIA study: The applicant submitted a two part study (Study 1097) with two goals. The goal of the first part was to “describe treatments and patterns of use in males with MBC in the U.S. by utilizing a comprehensive data source.” The second part of Study 1097 sought to determine “whether the exclusion of male patients from the current approved indication is a factor in the number of males having access, and ultimately being treated with palbociclib.”

Postmarketing data: The applicant provided postmarketing data from a variety of sources to provide more information on palbociclib’s safety profile.

Protocols for RWE generation
Flatiron study: The applicant engaged Flatiron Health to provide RWE from electronic health record (EHR) data. The applicant conducted a retrospective analysis of the EHR data, establishing two cohorts. Cohort A was based on receipt of palbociclib in any line of therapy, and cohort B included patients never prescribed palbociclib but who had received an endocrine therapy treatment regimen. Following the application of various exclusion criteria, the palbociclib cohort contained 25 patients, and the endocrine therapy alone cohort contained 34 patients. The primary outcome was real-world treatment response rate. The applicant collected pre-specified safety events for cohort A only.

IQVIA study: The applicant conducted this study in two parts. The first part used IQVIA’s pharmacy claims and medical claims database to conduct a linked retrospective analysis. The second part used pharmacy adjudication experience (FIA) data. The primary outcome of the study was prescription duration.

Postmarketing data: The applicant used its global safety database to search for adverse events (AEs) in male patients receiving palbociclib. The applicant found 362 cases, 60 of which reported serious AEs. The applicant also provided Periodic Adverse Drug Experience Reports (PADERs) from November 3, 2017, to February 2, 2018. These reports included 2,506 cases (62 males), 205 of which reported fatal events (11 males). To supplement these reports, the FDA conducted a review of the FDA Adverse Event Reporting System (FAERS) and a literature search. The review of the FAERS database returned 23,251 reports (569 male). The literature review provided four studies involving male and female patients treated with palbociclib.

Outcome of the RWE submissions
Flatiron study: The FDA discussed a number of issues with the RWE study, noting a limited sample size, that the applicant did not use matching or propensity scores to reduce bias between the two cohorts, and that the cohorts were not well-balanced with respect to age or treatment experience. Despite the issues, the FDA found that the Flatiron study, when evaluated in the context of the PALOMA-2 study results, provided supportive evidence of efficacy for the use of palbociclib in male breast cancer patients. The FDA stated “while these results provided supportive evidence, the Flatiron study did not provide definitive evidence to conclude that palbociclib adds to the anti-tumor activity of endocrine therapy alone.” The FDA also concluded that “given the extensive established efficacy and safety of the use of palbociclib in women observed in randomized clinical trials, the additional EHR data provided in this application for the use in men, modest as it is, does support the expansion of the palbociclib indication to provide for the treatment of men with metastatic breast cancer.”

IQVIA study: The FDA noted a number of issues with the study. The agency stated it was unclear whether “the data are confounded or balanced regarding baseline covariates.” When examining the study’s primary endpoint, the FDA noted that “the usefulness of the prescription duration in evaluating efficacy is unclear.” Accordingly, the FDA concluded it “did not consider the IQVIA study results in the benefit/risk assessment.”

Postmarketing data: The postmarketing data did not result in any new safety signals. The reviewer stated that the data “revealed no new safety signals in male breast cancer patients and in general, the AE profile for male patients appears to be consistent with the known AE profile of palbociclib.”

FDA Decision Alerts

Subscribe to our FDA Decision Alerts for emails as we add new summaries of RWE used in FDA decisions to our library.

eBook

The role of real-world evidence in FDA approvals

View now
arrowcalendarchevronclosecollapsecountdownfacebookflickrinstagramlinelinkedinlocationpinsearchsocialtwitteryoutube