Tocilizumab in rheumatoid arthritis: A case study of safety evaluations of a large postmarketing data set from multiple data sources

https://doi.org/10.1016/j.semarthrit.2014.07.006Get rights and content
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Abstract

Objectives

To evaluate the magnitude of serious adverse events (SAEs) observed in postmarketing reports of tocilizumab (TCZ) for rheumatoid arthritis (RA) in relation to SAEs observed in TCZ clinical trials and external epidemiology data.

Methods

A total of 64,000 patient-years (PY) of TCZ exposure was needed to determine, with 90% power, whether rates of SAEs of interest (eg, death, hepatic, gastrointestinal, and cardiovascular) were ≥50% higher (agreed with the Food and Drug Administration) than expected. Reporting rates were calculated for spontaneously reported SAEs, open-label or unblinded postmarketing clinical trials (phase 3b/4), and a Japanese postmarketing surveillance program in the global postmarketing safety database. Event rates were calculated for the registrational placebo-controlled trials and long-term extension data. External comparators for anti-tumor necrosis factor (aTNF)-treated RA patients were derived from a US-based health care insurance claims database or published literature.

Results

The global postmarketing safety database provided 65,099 PY of TCZ exposure; the aTNF external comparator population provided 53,360 PY. Spontaneous reporting rates per 100 PY (95% confidence interval) were 8.3 (8.1, 8.5) SAEs, 0.39 (0.34, 0.44) deaths, 0.06 (0.04, 0.08) serious hepatic events, 0.15 (0.12, 0.18) serious gastrointestinal events, 0.09 (0.07, 0.12) serious myocardial infarctions, 0.15 (0.12, 0.18) serious strokes, and 0.07 (0.05, 0.09) cardiac deaths in the global postmarketing safety database. These were of similar magnitude to corresponding rates from registrational clinical trials, the aTNF external comparator population, and published literature.

Conclusions

SAE rates observed among postmarketing TCZ users were similar to those of various comparison populations. Predetermined design of studies to compare postmarketing AEs using multiple data sources is a useful strategy that can be applied to other medications.

Keywords

Tocilizumab
Rheumatoid arthritis
Serious adverse events
Postmarketing

Cited by (0)

This evaluation was funded by F. Hoffmann-La Roche Ltd. The organization was responsible for the study design in collaboration with the authors. The sponsor collected, analyzed, and interpreted the data, with the authors contributing to data interpretation and the drafting/revising of the manuscript. The authors attest to the accuracy and completeness of the reported data and had final responsibility for the decision to submit the manuscript for publication.

Susanne Pérez-Gutthann is a researcher with RTI Health Solutions, a business unit of RTI International, which receives grants from and has consultation contracts with Genentech/Roche, Iroko, and Helsinn; she also chairs the Actemra Pharmacoepidemiology Board. Samy Suissa has received fees for travel to meetings and for participation on data monitoring boards for Genentech/Roche and Bristol–Myers Squibb; he also is a researcher at McGill University, which receives grants from Boehringer-Ingelheim. Jeffrey R Curtis is a consultant to Genentech/Roche and has received grants from UCB, Janssen, CORRONA, Amgen, Pfizer, Bristol–Myers Squibb, Crescendo Biosciences, and AbbVie. Pavel Napalkov is an employee of and a stockholder in Genentech, a member of the Roche group. Natasha Singh is an employee of Genentech, a member of the Roche group. Liz Thompson is an employee of and a stockholder in Roche Products Ltd. Benjamin Porter-Brown is an employee of and a stockholder in Roche Products Ltd.